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Sample records for polygenic mouse model

  1. Improving glucose tolerance by reducing weight gain in a polygenic obese mouse model: use of a high protein diet.

    PubMed

    Blair, A R; Strube, M L; Proietto, J; Andrikopoulos, S

    2015-03-01

    Diets to decrease body weight have limited success in achieving and importantly maintaining this weight loss long-term. It has recently been suggested that energy intake can be regulated by the amount of protein ingested, termed the protein leverage hypothesis. In this study, we determined whether a high protein diet would be effective in achieving and maintaining weight loss in a genetically obese model, the New Zealand Obese (NZO) mouse. NZO and C57BL/6J (C57) control mice were fed a high protein or chow diet for 5 weeks from weaning (3 weeks of age). Body weight and food intake were determined. Mice on the same diet were bred to produce offspring that were fed either a chow or high protein diet. Body weight, food intake, and glucose tolerance were determined. Feeding NZO and C57 mice a high protein diet for 5 weeks resulted in reduced food intake and consequently energy intake and body weight gain compared with mice on a chow diet. NZO mice fed a high protein diet showed a significant improvement in glucose tolerance compared with their chow-fed counterparts, while no difference was seen in C57 mice fed chow or protein diet. The offspring of NZO mice that were fed a high protein diet during gestation and weaning were also lighter and displayed improved glucose tolerance compared with chow fed animals. We conclude that a high protein diet is a reasonable strategy to reduce body weight gain and improve glucose tolerance in the NZO mouse, a polygenic model of obesity.

  2. Rapamycin Ameliorates Nephropathy despite Elevating Hyperglycemia in a Polygenic Mouse Model of Type 2 Diabetes, NONcNZO10/LtJ

    PubMed Central

    Reifsnyder, Peter C.; Doty, Rosalinda; Harrison, David E.

    2014-01-01

    While rapamycin treatment has been reported to have a putatively negative effect on glucose homeostasis in mammals, it has not been tested in polygenic models of type 2 diabetes. One such mouse model, NONcNZO10/LtJ, was treated chronically with rapamycin (14 ppm encapsulated in diet) and monitored for the development of diabetes. As expected, rapamycin treatment accelerated the onset and severity of hyperglycemia. However, development of nephropathy was ameliorated, as both glomerulonephritis and IgG deposition in the subendothelial tuft were markedly reduced. Insulin production and secretion appeared to be inhibited, suppressing the developing hyperinsulinemia present in untreated controls. Rapamycin treatment also reduced body weight gain. Thus, rapamycin reduced some of the complications of diabetes despite elevating hyperglycemia. These results suggest that multiple factors must be evaluated when assessing the benefit vs. hazard of rapamycin treatment in patients that have overt, or are at risk for, type 2 diabetes. Testing of rapamycin in combination with insulin sensitizers is warranted, as such compounds may ameliorate the putative negative effects of rapamycin in the type 2 diabetes environment. PMID:25473963

  3. Technical note: Equivalent genomic models with a residual polygenic effect.

    PubMed

    Liu, Z; Goddard, M E; Hayes, B J; Reinhardt, F; Reents, R

    2016-03-01

    Routine genomic evaluations in animal breeding are usually based on either a BLUP with genomic relationship matrix (GBLUP) or single nucleotide polymorphism (SNP) BLUP model. For a multi-step genomic evaluation, these 2 alternative genomic models were proven to give equivalent predictions for genomic reference animals. The model equivalence was verified also for young genotyped animals without phenotypes. Due to incomplete linkage disequilibrium of SNP markers to genes or causal mutations responsible for genetic inheritance of quantitative traits, SNP markers cannot explain all the genetic variance. A residual polygenic effect is normally fitted in the genomic model to account for the incomplete linkage disequilibrium. In this study, we start by showing the proof that the multi-step GBLUP and SNP BLUP models are equivalent for the reference animals, when they have a residual polygenic effect included. Second, the equivalence of both multi-step genomic models with a residual polygenic effect was also verified for young genotyped animals without phenotypes. Additionally, we derived formulas to convert genomic estimated breeding values of the GBLUP model to its components, direct genomic values and residual polygenic effect. Third, we made a proof that the equivalence of these 2 genomic models with a residual polygenic effect holds also for single-step genomic evaluation. Both the single-step GBLUP and SNP BLUP models lead to equal prediction for genotyped animals with phenotypes (e.g., reference animals), as well as for (young) genotyped animals without phenotypes. Finally, these 2 single-step genomic models with a residual polygenic effect were proven to be equivalent for estimation of SNP effects, too.

  4. Polygenic Epidemiology

    PubMed Central

    2016-01-01

    ABSTRACT Much of the genetic basis of complex traits is present on current genotyping products, but the individual variants that affect the traits have largely not been identified. Several traditional problems in genetic epidemiology have recently been addressed by assuming a polygenic basis for disease and treating it as a single entity. Here I briefly review some of these applications, which collectively may be termed polygenic epidemiology. Methodologies in this area include polygenic scoring, linear mixed models, and linkage disequilibrium scoring. They have been used to establish a polygenic effect, estimate genetic correlation between traits, estimate how many variants affect a trait, stratify cases into subphenotypes, predict individual disease risks, and infer causal effects using Mendelian randomization. Polygenic epidemiology will continue to yield useful applications even while much of the specific variation underlying complex traits remains undiscovered. PMID:27061411

  5. Linkage Analysis with an Alternative Formulation for the Mixed Model of Inheritance: The Finite Polygenic Mixed Model

    PubMed Central

    Stricker, C.; Fernando, R. L.; Elston, R. C.

    1995-01-01

    This paper presents an extension of the finite polygenic mixed model of FERNANDO et al. (1994) to linkage analysis. The finite polygenic mixed model, extended for linkage analysis, leads to a likelihood that can be calculated using efficient algorithms developed for oligogenic models. For comparison, linkage analysis of 5 simulated 4021-member pedigrees was performed using the usual mixed model of inheritance, approximated by HASSTEDT (1982), and the finite polygenic mixed model extended for linkage analysis presented here. Maximum likelihood estimates of the finite polygenic mixed model could be inferred to be closer to the simulated values in these pedigrees. PMID:8601502

  6. Polygenic formation model of the planet's bituminous belts

    NASA Astrophysics Data System (ADS)

    Dmitrievsky, A. N.; Balanyuk, I. E.

    2011-05-01

    In recent years, much attention has been paid to nontraditional hydrocarbon sources. Today the portion of nontraditional gas in the world extraction is 15% or 450 billion cubic meters, which hat makes up the volume of total gas exports from Russia. As is known, the easy-prospecting oil has been already found. The innovative technologies in geophysics, drilling, and excavation and the increased extraction coefficient expect further development and industrial compliance with these requirements. Based on calculations, the world oil reserves are now one trillion of stock tank barrels and one trillion barrels have been already extracted. The evergrowing demand for energy gives rise to the necessity of searching for and extracting more oil resources, and both these aspects are unique problems. The search for profitable petroleum deposits has become more and more difficult even in the leading companies. The increment of the world resources is a key vital question; therefore, the elaboration of criteria for the discovery of nontraditional deposits take on special significance in the economic respect. The authors are working out a conception that will be a guideline for future finding of the richest oil deposits in active geodynamic zones. For the first time, we suggest the polygenic formation model of the planet's bituminous belts.

  7. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.

    PubMed

    Vilhjálmsson, Bjarni J; Yang, Jian; Finucane, Hilary K; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Do, Ron; Hayeck, Tristan; Won, Hong-Hee; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Stahl, Eli; Zaitlen, Noah; Pasaniuc, Bogdan; Belbin, Gillian; Kenny, Eimear E; Schierup, Mikkel H; De Jager, Philip; Patsopoulos, Nikolaos A; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Neale, Benjamin; Goddard, Michael; Visscher, Peter M; Kraft, Peter; Patterson, Nick; Price, Alkes L

    2015-10-01

    Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

  8. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

    PubMed Central

    Vilhjálmsson, Bjarni J.; Yang, Jian; Finucane, Hilary K.; Gusev, Alexander; Lindström, Sara; Ripke, Stephan; Genovese, Giulio; Loh, Po-Ru; Bhatia, Gaurav; Do, Ron; Hayeck, Tristan; Won, Hong-Hee; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T.R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberly D.; Chan, Raymond C.K.; Chen, Ronald Y.L.; Chen, Eric Y.H.; Cheng, Wei; Cheung, Eric F.C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E.; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodrguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; Grove, Jakob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julia, Antonio; Kahn, Rene S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kahler, Anna K.; Laurent, Claudine; Keong, Jimmy Lee Chee; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lnnqvist, Jouko; Macek, Milan; Magnusson, Patrik K.E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Mortensen, Preben B.; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Mller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O’Callaghan, Eadbhard; O’Dushlaine, Colm; O’Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietilinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C.A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Sderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tooney, Paul A.; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H.M.; Wormley, Brandon K.; Wu, Jing Qin; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H.R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tonu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jonsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Nthen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St. Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O’Donovan, Michael C.; Kraft, Peter; Hunter, David J.; Adank, Muriel; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Berndt, Sonja; Blomquist, Carl; Canzian, Federico; Chang-Claude, Jenny; Chanock, Stephen J.; Crisponi, Laura; Czene, Kamila; Dahmen, Norbert; Silva, Isabel dos Santos; Easton, Douglas; Eliassen, A. Heather; Figueroa, Jonine; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Gibson, Lorna; Haiman, Christopher A.; Hall, Per; Hazra, Aditi; Hein, Rebecca; Henderson, Brian E.; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Lindström, Sara; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Meijers-Heijboer, Hanne; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sánchez, María José; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth; Turnbull, Clare; Uitterlinden, Andre G.; van der Luijt, Rob B.; Waisfisz, Quinten; Wang, Zhaoming; Whittemore, Alice S.; Yang, Rose; Zheng, Wei; Kathiresan, Sekar; Pato, Michele; Pato, Carlos; Tamimi, Rulla; Stahl, Eli; Zaitlen, Noah; Pasaniuc, Bogdan; Belbin, Gillian; Kenny, Eimear E.; Schierup, Mikkel H.; De Jager, Philip; Patsopoulos, Nikolaos A.; McCarroll, Steve; Daly, Mark; Purcell, Shaun; Chasman, Daniel; Neale, Benjamin; Goddard, Michael; Visscher, Peter M.; Kraft, Peter; Patterson, Nick; Price, Alkes L.

    2015-01-01

    Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. PMID:26430803

  9. Maintenance of polygenic sex determination in a fluctuating environment: An individual-based model.

    PubMed

    Bateman, Andrew W; Anholt, Bradley R

    2017-02-10

    R. A. Fisher predicted that individuals should invest equally in offspring of both sexes, and that the proportion of males and females produced (the primary sex ratio) should evolve towards 1:1 when unconstrained. For many species, sex determination is dependent on sex chromosomes, creating a strong tendency for balanced sex ratios, but in other cases multiple autosomal genes interact to determine sex. In such cases, the maintenance of multiple sex-determining alleles at multiple loci and the consequent between-family variability in sex ratios presents a puzzle, as theory predicts that such systems should be unstable. Theory also predicts that environmental influences on sex can complicate outcomes of genetic sex determination, and that population structure may play a role. Tigriopus californicus, a copepod that lives in splash-pool metapopulations and exhibits polygenic and environment-dependent sex determination, presents a test case for relevant theory. We use this species as a model for parameterizing an individual-based simulation to investigate conditions that could maintain polygenic sex determination. We find that metapopulation structure can delay the degradation of polygenic sex determination and that periods of alternating frequency-dependent selection, imposed by seasonal fluctuations in environmental conditions, can maintain polygenic sex determination indefinitely. This article is protected by copyright. All rights reserved.

  10. Estimating Polygenic Models for Multivariate Data on Large Pedigrees

    PubMed Central

    Thompson, E. A.; Shaw, R. G.

    1992-01-01

    We have developed algorithms for the likelihood estimation of additive genetic models for quantitative traits on large pedigrees. The approach uses the expectation L-maximization (EM) algorithm, but avoids intensive computation. In this paper, we focus on extensions of previous work to the case of multivariate data. We exemplify the approach by analyses of bivariate data on a four-generation, 949-member pedigree of the snail Lymnaea elodes, and on a three-generation pedigree of the guppy Poecilia reticulata containing about 400 individuals. PMID:1516823

  11. [Psoriasis SCID-mouse model].

    PubMed

    Pfeffer, J; Kaufmann, R; Boehncke, W-H

    2006-07-01

    Psoriasis is characterized by a complex phenotype and pathogenesis along with polygenic determination. Several psoriasis animal models have only been able to incompletely reproduce the disease. A xenogeneic transplantation approach, grafting skin from psoriatic patients onto mice with a severe combined immunodeficiency (SCID), was the first to meet the criteria for a psoriasis model. During the last 10 years, this psoriasis SCID-mouse model not only allowed telling experiments focusing on pathogenetic aspects, but also proved being a powerful tool for drug discovery with a good predictive value.

  12. Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk.

    PubMed

    Birnbaum, Rebecca; Weinberger, Daniel R

    2013-09-01

    We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.

  13. A latent variable partial least squares path modeling approach to regional association and polygenic effect with applications to a human obesity study.

    PubMed

    Xue, Fuzhong; Li, Shengxu; Luan, Jian'an; Yuan, Zhongshang; Luben, Robert N; Khaw, Kay-Tee; Wareham, Nicholas J; Loos, Ruth J F; Zhao, Jing Hua

    2012-01-01

    Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609∼rs9939881 at the first intron P = 4.29×10(-7)) than single SNP analysis (all with P>10(-4)) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits.

  14. Mouse models in oncoimmunology.

    PubMed

    Zitvogel, Laurence; Pitt, Jonathan M; Daillère, Romain; Smyth, Mark J; Kroemer, Guido

    2016-12-01

    Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies - each with their specific advantages and difficulties - have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers. Specific aspects of pharmacological development, as well as attempts to personalize cancer treatments using patient-derived xenografts, require the development of mouse models in which murine genes and cells are replaced with their human equivalents. Such 'humanized' mouse models are being progressively refined to characterize the leukocyte subpopulations that belong to the innate and acquired arms of the immune system as they infiltrate human cancers that are subjected to experimental therapies. We surmise that the ever-advancing refinement of murine preclinical models will accelerate the pace of therapeutic optimization in patients.

  15. Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains

    PubMed Central

    Grainger, Andrew T.; Jones, Michael B.; Chen, Mei-Hua; Shi, Weibin

    2016-01-01

    Atherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid atherosclerosis in mice. From an intercross between BALB/cJ (BALB) and SM/J (SM) apolipoprotein E-deficient (Apoe−/−) mice, 228 female F2 mice were generated and fed a “Western” diet for 12 wk. Atherosclerotic lesion sizes in the left carotid artery were quantified. Across the entire genome, 149 genetic markers were genotyped. Quantitative trait locus (QTL) analysis revealed eight loci for carotid lesion sizes, located on chromosomes 1, 5, 12, 13, 15, 16, and 18. Combined cross-linkage analysis using data from this cross, and two previous F2 crosses derived from BALB, C57BL/6J and C3H/HeJ strains, identified five significant QTL on chromosomes 5, 9, 12, and 13, and nine suggestive QTL for carotid atherosclerosis. Of them, the QTL on chromosome 12 had a high LOD score of 9.95. Bioinformatic analysis prioritized Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 as probable candidate genes for this QTL. Atherosclerotic lesion sizes were significantly correlated with non-HDL cholesterol levels (r = 0.254; p = 0.00016) but inversely correlated with HDL cholesterol levels (r = −0.134; p = 0.049) in the current cross. Thus, we demonstrated the polygenic control of carotid atherosclerosis in mice. The correlations of carotid lesion sizes with non-HDL and HDL suggest that genetic factors exert effects on carotid atherosclerosis partially through modulation of lipoprotein homeostasis. PMID:28040783

  16. Polygenic Score × Intervention Moderation: an Application of Discrete-Time Survival Analysis to Model the Timing of First Marijuana Use Among Urban Youth.

    PubMed

    Musci, Rashelle J; Fairman, Brian; Masyn, Katherine E; Uhl, George; Maher, Brion; Sisto, Danielle Y; Kellam, Sheppard G; Ialongo, Nicholas S

    2016-11-05

    The present study examines the interaction between a polygenic score and an elementary school-based universal preventive intervention trial and its effects on a discrete-time survival analysis of time to first smoking marijuana. Research has suggested that initiation of substances is both genetically and environmentally driven (Rhee et al., Archives of general psychiatry 60:1256-1264, 2003; Verweij et al., Addiction 105:417-430, 2010). A previous work has found a significant interaction between the polygenic score and the same elementary school-based intervention with tobacco smoking (Musci et al., in press). The polygenic score reflects the contribution of multiple genes and has been shown in prior research to be predictive of smoking cessation, tobacco use, and marijuana use (Uhl et al., Molecular Psychiatry 19:50-54, 2014). Using data from a longitudinal preventive intervention study (N = 678), we examined age of first marijuana use from sixth grade to age 18. Genetic data were collected during emerging adulthood and were genotyped using the Affymetrix 6.0 microarray (N = 545). The polygenic score was computed using these data. Discrete-time survival analysis was employed to test for intervention main and interaction effects with the polygenic score. We found main effect of the polygenic score approaching significance, with the participants with higher polygenic scores reporting their first smoking marijuana at an age significantly later than controls (p = .050). We also found a significant intervention × polygenic score interaction effect at p = .003, with participants at the higher end of the polygenic score benefiting the most from the intervention in terms of delayed age of first use. These results suggest that genetics may play an important role in the age of first use of marijuana and that differences in genetics may account for the differential effectiveness of classroom-based interventions in delaying substance use experimentation.

  17. Common polygenic variation enhances risk prediction for Alzheimer's disease.

    PubMed

    Escott-Price, Valentina; Sims, Rebecca; Bannister, Christian; Harold, Denise; Vronskaya, Maria; Majounie, Elisa; Badarinarayan, Nandini; Morgan, Kevin; Passmore, Peter; Holmes, Clive; Powell, John; Brayne, Carol; Gill, Michael; Mead, Simon; Goate, Alison; Cruchaga, Carlos; Lambert, Jean-Charles; van Duijn, Cornelia; Maier, Wolfgang; Ramirez, Alfredo; Holmans, Peter; Jones, Lesley; Hardy, John; Seshadri, Sudha; Schellenberg, Gerard D; Amouyel, Philippe; Williams, Julie

    2015-12-01

    The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes.

  18. Mouse models for neurological disease.

    PubMed

    Hafezparast, Majid; Ahmad-Annuar, Azlina; Wood, Nicholas W; Tabrizi, Sarah J; Fisher, Elizabeth M C

    2002-08-01

    The mouse has many advantages over human beings for the study of genetics, including the unique property that genetic manipulation can be routinely carried out in the mouse genome. Most importantly, mice and human beings share the same mammalian genes, have many similar biochemical pathways, and have the same diseases. In the minority of cases where these features do not apply, we can still often gain new insights into mouse and human biology. In addition to existing mouse models, several major programmes have been set up to generate new mouse models of disease. Alongside these efforts are new initiatives for the clinical, behavioural, and physiological testing of mice. Molecular genetics has had a major influence on our understanding of the causes of neurological disorders in human beings, and much of this has come from work in mice.

  19. Mouse Models of Gastric Carcinogenesis

    PubMed Central

    Yu, Sungsook; Yang, Mijeong

    2014-01-01

    Gastric cancer is one of the most common cancers in the world. Animal models have been used to elucidate the details of the molecular mechanisms of various cancers. However, most inbred strains of mice have resistance to gastric carcinogenesis. Helicobacter infection and carcinogen treatment have been used to establish mouse models that exhibit phenotypes similar to those of human gastric cancer. A large number of transgenic and knockout mouse models of gastric cancer have been developed using genetic engineering. A combination of carcinogens and gene manipulation has been applied to facilitate development of advanced gastric cancer; however, it is rare for mouse models of gastric cancer to show aggressive, metastatic phenotypes required for preclinical studies. Here, we review current mouse models of gastric carcinogenesis and provide our perspectives on future developments in this field. PMID:25061535

  20. Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data

    PubMed Central

    Shi, Jianxin; Duan, Jubao; Berndt, Sonja T.; Moy, Winton; Yu, Kai; Song, Lei; Wheeler, William; Hua, Xing; Silverman, Debra; Garcia-Closas, Montserrat; Hsiung, Chao Agnes; Figueroa, Jonine D.; Cortessis, Victoria K.; Malats, Núria; Karagas, Margaret R.; Vineis, Paolo; Chang, I-Shou; Lin, Dongxin; Zhou, Baosen; Seow, Adeline; Hong, Yun-Chul; Caporaso, Neil E.; Wolpin, Brian; Jacobs, Eric; Petersen, Gloria M.; Klein, Alison P.; Li, Donghui; Risch, Harvey; Sanders, Alan R.; Hsu, Li; Schoen, Robert E.; Brenner, Hermann; Stolzenberg-Solomon, Rachael; Gejman, Pablo; Lan, Qing; Rothman, Nathaniel; Amundadottir, Laufey T.; Landi, Maria Teresa; Levinson, Douglas F.; Chanock, Stephen J.; Chatterjee, Nilanjan

    2016-01-01

    Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner’s-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner’s curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25–50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner’s curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10−5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure. PMID:28036406

  1. Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data.

    PubMed

    Shi, Jianxin; Park, Ju-Hyun; Duan, Jubao; Berndt, Sonja T; Moy, Winton; Yu, Kai; Song, Lei; Wheeler, William; Hua, Xing; Silverman, Debra; Garcia-Closas, Montserrat; Hsiung, Chao Agnes; Figueroa, Jonine D; Cortessis, Victoria K; Malats, Núria; Karagas, Margaret R; Vineis, Paolo; Chang, I-Shou; Lin, Dongxin; Zhou, Baosen; Seow, Adeline; Matsuo, Keitaro; Hong, Yun-Chul; Caporaso, Neil E; Wolpin, Brian; Jacobs, Eric; Petersen, Gloria M; Klein, Alison P; Li, Donghui; Risch, Harvey; Sanders, Alan R; Hsu, Li; Schoen, Robert E; Brenner, Hermann; Stolzenberg-Solomon, Rachael; Gejman, Pablo; Lan, Qing; Rothman, Nathaniel; Amundadottir, Laufey T; Landi, Maria Teresa; Levinson, Douglas F; Chanock, Stephen J; Chatterjee, Nilanjan

    2016-12-01

    Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R2 to 3.53% (P = 2×10-5). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure.

  2. Mouse models for graft arteriosclerosis.

    PubMed

    Qin, Lingfeng; Yu, Luyang; Min, Wang

    2013-05-14

    Graft arteriosclerois (GA), also called allograft vasculopathy, is a pathologic lesion that develops over months to years in transplanted organs characterized by diffuse, circumferential stenosis of the entire graft vascular tree. The most critical component of GA pathogenesis is the proliferation of smooth muscle-like cells within the intima. When a human coronary artery segment is interposed into the infra-renal aortae of immunodeficient mice, the intimas could be expand in response to adoptively transferred human T cells allogeneic to the artery donor or exogenous human IFN-γ in the absence of human T cells. Interposition of a mouse aorta from one strain into another mouse strain recipient is limited as a model for chronic rejection in humans because the acute cell-mediated rejection response in this mouse model completely eliminates all donor-derived vascular cells from the graft within two-three weeks. We have recently developed two new mouse models to circumvent these problems. The first model involves interposition of a vessel segment from a male mouse into a female recipient of the same inbred strain (C57BL/6J). Graft rejection in this case is directed only against minor histocompatibility antigens encoded by the Y chromosome (present in the male but not the female) and the rejection response that ensues is sufficiently indolent to preserve donor-derived smooth muscle cells for several weeks. The second model involves interposing an artery segment from a wild type C57BL/6J mouse donor into a host mouse of the same strain and gender that lacks the receptor for IFN-γ followed by administration of mouse IFN-γ (delivered via infection of the mouse liver with an adenoviral vector. There is no rejection in this case as both donor and recipient mice are of the same strain and gender but donor smooth muscle cells proliferate in response to the cytokine while host-derived cells, lacking receptor for this cytokine, are unresponsive. By backcrossing additional

  3. Mouse Models of Rheumatoid Arthritis.

    PubMed

    Caplazi, P; Baca, M; Barck, K; Carano, R A D; DeVoss, J; Lee, W P; Bolon, B; Diehl, L

    2015-09-01

    Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFΔ (ARE) mouse, in which arthritis results from overexpression of TNF-α, a master proinflammatory cytokine that drives disease in many patients.

  4. Mouse models of myasthenia gravis.

    PubMed

    Ban, Joanne; Phillips, William D

    2015-01-01

    Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

  5. Fingerprint Ridge Count: A Polygenic Trait Useful in Classroom Instruction.

    ERIC Educational Resources Information Center

    Mendenhall, Gordon; And Others

    1989-01-01

    Describes the use of the polygenic trait of total fingerprint ridge count in the classroom as a laboratory investigation. Presents information on background of topic, fingerprint patterns which are classified into three major groups, ridge count, the inheritance model, and activities. Includes an example data sheet format for fingerprints. (RT)

  6. A Population Genetic Signal of Polygenic Adaptation

    PubMed Central

    Berg, Jeremy J.; Coop, Graham

    2014-01-01

    Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results. PMID:25102153

  7. Mouse Models of Human Phenylketonuria

    PubMed Central

    Shedlovsky, A.; McDonald, J. D.; Symula, D.; Dove, W. F.

    1993-01-01

    Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy. PMID:8375656

  8. Mouse Models for Methylmalonic Aciduria

    PubMed Central

    Peters, Heidi L.; Pitt, James J.; Wood, Leonie R.; Hamilton, Natasha J.; Sarsero, Joseph P.; Buck, Nicole E.

    2012-01-01

    Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of methylmalonyl-CoA mutase (MCM). MMA is associated with significant morbidity and mortality, thus therapies are necessary to help improve quality of life and prevent renal and neurological complications. Transgenic mice carrying an intact human MCM locus have been produced. Four separate transgenic lines were established and characterised as carrying two, four, five or six copies of the transgene in a single integration site. Transgenic mice from the 2-copy line were crossed with heterozygous knockout MCM mice to generate mice hemizygous for the human transgene on a homozygous knockout background. Partial rescue of the uniform neonatal lethality seen in homozygous knockout mice was observed. These rescued mice were significantly smaller than control littermates (mice with mouse MCM gene). Biochemically, these partial rescue mice exhibited elevated methylmalonic acid levels in urine, plasma, kidney, liver and brain tissue. Acylcarnitine analysis of blood spots revealed elevated propionylcarnitine levels. Analysis of mRNA expression confirms the human transgene is expressed at higher levels than observed for the wild type, with highest expression in the kidney followed closely by brain and liver. Partial rescue mouse fibroblast cultures had only 20% of the wild type MCM enzyme activity. It is anticipated that this humanised partial rescue mouse model of MMA will enable evaluation of long-term pathophysiological effects of elevated methylmalonic acid levels and be a valuable model for the investigation of therapeutic strategies, such as cell transplantation. PMID:22792386

  9. Aging Research Using Mouse Models.

    PubMed

    Ackert-Bicknell, Cheryl L; Anderson, Laura C; Sheehan, Susan; Hill, Warren G; Chang, Bo; Churchill, Gary A; Chesler, Elissa J; Korstanje, Ron; Peters, Luanne L

    2015-06-01

    Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in "health-span," or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, and immune function, as well as physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process.

  10. Aging Research Using Mouse Models

    PubMed Central

    Ackert-Bicknell, Cheryl L.; Anderson, Laura; Sheehan, Susan; Hill, Warren G.; Chang, Bo; Churchill, Gary A.; Chesler, Elissa J.; Korstanje, Ron; Peters, Luanne L.

    2015-01-01

    Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in “health-span”, or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, immune function and physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process. PMID:26069080

  11. Mouse Models of Tumor Immunotherapy.

    PubMed

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.

  12. Mouse Models of Alzheimer's Disease.

    PubMed

    Esquerda-Canals, Gisela; Montoliu-Gaya, Laia; Güell-Bosch, Jofre; Villegas, Sandra

    2017-03-10

    Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology. Then, transgenic mouse lines harboring mutated human genes at several loci such as APP, PSEN1, APOEɛ4, and ob (leptin) are reviewed. Therefore, not only the accumulation of the Aβ peptide is emulated but also cholesterol and insulin metabolism. Further novel information about the disease will allow for the development of more accurate animal models, which in turn will undoubtedly be helpful for bringing preclinical research closer to clinical trials in humans.

  13. Mouse models of human thalassemia

    SciTech Connect

    Anderson, W.F.; Martinell, J.; Whitney, J.B. III; Popp, R.A.

    1981-01-01

    The group of diseases called the thalassemias is the largest single-gene health problem in the world according the World Health Organization. The thalassemias are lethal hereditary anemias in which the infants cannot make their own blood. Three mouse mutants are shown to be models of the human disease ..cap alpha..-thalassemia. However, since an additional gene is affected, these mutants represent a particularly severe condition in which death occurs in the homozygous embryo even before globin genes are activated. Phenotypic and genotypic characteristics are described. (ACR)

  14. Genetic mouse models of depression.

    PubMed

    Barkus, Christopher

    2013-01-01

    This chapter focuses on the use of genetically modified mice in investigating the neurobiology of depressive behaviour. First, the behavioural tests commonly used as a model of depressive-like behaviour in rodents are described. These tests include those sensitive to antidepressant treatment such as the forced swim test and the tail suspension test, as well as other tests that encompass the wider symptomatology of a depressive episode. A selection of example mutant mouse lines is then presented to illustrate the use of these tests. As our understanding of depression increases, an expanding list of candidate genes is being investigated using mutant mice. Here, mice relevant to the monoamine and corticotrophin-releasing factor hypotheses of depression are covered as well as those relating to the more recent candidate, brain-derived neurotrophic factor. This selection provides interesting examples of the use of complimentary lines, such as those that have genetic removal or overexpression, and also opposing behavioural changes seen following manipulation of closely related genes. Finally, factors such as the issue of background strain and influence of environmental factors are reflected upon, before considering what can realistically be expected of a mouse model of this complex psychiatric disorder.

  15. Common polygenic variation enhances risk prediction for Alzheimer’s disease

    PubMed Central

    Sims, Rebecca; Bannister, Christian; Harold, Denise; Vronskaya, Maria; Majounie, Elisa; Badarinarayan, Nandini; Morgan, Kevin; Passmore, Peter; Holmes, Clive; Powell, John; Brayne, Carol; Gill, Michael; Mead, Simon; Goate, Alison; Cruchaga, Carlos; Lambert, Jean-Charles; van Duijn, Cornelia; Maier, Wolfgang; Ramirez, Alfredo; Holmans, Peter; Jones, Lesley; Hardy, John; Seshadri, Sudha; Schellenberg, Gerard D.; Amouyel, Philippe

    2015-01-01

    The identification of subjects at high risk for Alzheimer’s disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer’s disease and the accuracy of Alzheimer’s disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer’s Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer’s disease (P = 4.9 × 10−26). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10−19). The best prediction accuracy AUC = 78.2% (95% confidence interval 77–80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer’s disease has a significant polygenic component, which has predictive utility for Alzheimer’s disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes. PMID:26490334

  16. Personality Polygenes, Positive Affect, and Life Satisfaction.

    PubMed

    Weiss, Alexander; Baselmans, Bart M L; Hofer, Edith; Yang, Jingyun; Okbay, Aysu; Lind, Penelope A; Miller, Mike B; Nolte, Ilja M; Zhao, Wei; Hagenaars, Saskia P; Hottenga, Jouke-Jan; Matteson, Lindsay K; Snieder, Harold; Faul, Jessica D; Hartman, Catharina A; Boyle, Patricia A; Tiemeier, Henning; Mosing, Miriam A; Pattie, Alison; Davies, Gail; Liewald, David C; Schmidt, Reinhold; De Jager, Philip L; Heath, Andrew C; Jokela, Markus; Starr, John M; Oldehinkel, Albertine J; Johannesson, Magnus; Cesarini, David; Hofman, Albert; Harris, Sarah E; Smith, Jennifer A; Keltikangas-Järvinen, Liisa; Pulkki-Råback, Laura; Schmidt, Helena; Smith, Jacqui; Iacono, William G; McGue, Matt; Bennett, David A; Pedersen, Nancy L; Magnusson, Patrik K E; Deary, Ian J; Martin, Nicholas G; Boomsma, Dorret I; Bartels, Meike; Luciano, Michelle

    2016-10-01

    Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.

  17. Mouse models of intracranial aneurysm.

    PubMed

    Wang, Yutang; Emeto, Theophilus I; Lee, James; Marshman, Laurence; Moran, Corey; Seto, Sai-wang; Golledge, Jonathan

    2015-05-01

    Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-α, the renin-angiotensin system and the β-estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients.

  18. Mouse models of adrenocortical tumors

    PubMed Central

    Basham, Kaitlin J.; Hung, Holly A.; Lerario, Antonio M.; Hammer, Gary D.

    2016-01-01

    The molecular basis of the organogenesis, homeostasis, and tumorigenesis of the adrenal cortex has been the subject of intense study for many decades. Specifically, characterization of tumor predisposition syndromes with adrenocortical manifestations and molecular profiling of sporadic adrenocortical tumors have led to the discovery of key molecular pathways that promote pathological adrenal growth. However, given the observational nature of such studies, several important questions regarding the molecular pathogenesis of adrenocortical tumors have remained. This review will summarize naturally occurring and genetically engineered mouse models that have provided novel tools to explore the molecular and cellular underpinnings of adrenocortical tumors. New paradigms of cancer initiation, maintenance, and progression that have emerged from this work will be discussed. PMID:26678830

  19. Mouse Models for Filovirus Infections

    PubMed Central

    Bradfute, Steven B.; Warfield, Kelly L.; Bray, Mike

    2012-01-01

    The filoviruses marburg- and ebolaviruses can cause severe hemorrhagic fever (HF) in humans and nonhuman primates. Because many cases have occurred in geographical areas lacking a medical research infrastructure, most studies of the pathogenesis of filoviral HF, and all efforts to develop drugs and vaccines, have been carried out in biocontainment laboratories in non-endemic countries, using nonhuman primates (NHPs), guinea pigs and mice as animal models. NHPs appear to closely mirror filoviral HF in humans (based on limited clinical data), but only small numbers may be used in carefully regulated experiments; much research is therefore done in rodents. Because of their availability in large numbers and the existence of a wealth of reagents for biochemical and immunological testing, mice have become the preferred small animal model for filovirus research. Since the first experiments following the initial 1967 marburgvirus outbreak, wild-type or mouse-adapted viruses have been tested in immunocompetent or immunodeficient mice. In this paper, we review how these types of studies have been used to investigate the pathogenesis of filoviral disease, identify immune responses to infection and evaluate antiviral drugs and vaccines. We also discuss the strengths and weaknesses of murine models for filovirus research, and identify important questions for further study. PMID:23170168

  20. Mouse models of sickle cell disease.

    PubMed

    Beuzard, Y

    2008-01-01

    In the absence of a natural animal model for sickle cell disease, transgenic mouse models have been generated to better understand the complex pathophysiology of the disease and to evaluate potential specific therapies. In the early nineties, the simple addition of human globin genes induced the expression of hemoglobin S (HbS) or HbS-related human hemoglobins in mice still expressing mouse hemoglobin. To increase the proportion of human hemoglobin and the severity of the mouse sickle cell syndrome, the proportion of mouse hemoglobin could be decreased by a combination of mouse alpha- and beta-thalassemic defects, leading to complex genotypes and mild disease. Following the discovery of gene targeting in the mouse embryonic stem cells (ES cells), it was made possible to knock out all mouse adult globin genes (2alpha and 2beta) and to add the human homologous genes elsewhere in the mouse genome. In addition, the human gamma gene of fetal hemoglobin was protecting the fetus from HbS polymer formation. Accordingly, the resulting adult mouse models obtained in 1997, expressing human HbS-only, had a very severe anemia (Hb=5-6 g/dL). In order to survive, these "HbS-only mice" had to reduce the HbS concentration within the red blood cells. The phenotype could be less severe by adding modified human gamma genes, still expressed in adult mice. In 2006, a last "S-only" model was obtained by homologous knock in, replacing the mouse globin genes by human genes. This array of models contributes to better understand the role of different interacting factors in the complexity of sickle cell events, such as red cell defects, changes in blood flow and vaso-occlusion, hyperhemolysis, vascular tone dysregulation, oxidations, inflammation, activation and adhesion of cells, ischemia, reperfusion... In addition, each model has an appropriate usefulness to evaluate experimental therapies in vivo and to perform preclinical studies.

  1. Polygenic Sex Determination System in Zebrafish

    PubMed Central

    Liew, Woei Chang; Bartfai, Richard; Lim, Zijie; Sreenivasan, Rajini; Siegfried, Kellee R.; Orban, Laszlo

    2012-01-01

    Background Despite the popularity of zebrafish as a research model, its sex determination (SD) mechanism is still unknown. Most cytogenetic studies failed to find dimorphic sex chromosomes and no primary sex determining switch has been identified even though the assembly of zebrafish genome sequence is near to completion and a high resolution genetic map is available. Recent publications suggest that environmental factors within the natural range have minimal impact on sex ratios of zebrafish populations. The primary aim of this study is to find out more about how sex is determined in zebrafish. Methodology/Principal Findings Using classical breeding experiments, we found that sex ratios across families were wide ranging (4.8% to 97.3% males). On the other hand, repeated single pair crossings produced broods of very similar sex ratios, indicating that parental genotypes have a role in the sex ratio of the offspring. Variation among family sex ratios was reduced after selection for breeding pairs with predominantly male or female offspring, another indication that zebrafish sex is regulated genetically. Further examinations by a PCR-based “blind assay" and array comparative genomic hybridization both failed to find universal sex-linked differences between the male and female genomes. Together with the ability to increase the sex bias of lines by selective breeding, these data suggest that zebrafish is unlikely to utilize a chromosomal sex determination (CSD) system. Conclusions/Significance Taken together, our study suggests that zebrafish sex is genetically determined with limited, secondary influences from the environment. As we have not found any sign for CSD in the species, we propose that the zebrafish has a polygenic sex determination system. PMID:22506019

  2. Melatonin receptors: latest insights from mouse models

    PubMed Central

    Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

    2014-01-01

    Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

  3. Mouse models in tendon and ligament research.

    PubMed

    Mienaltowski, Michael J; Birk, David E

    2014-01-01

    Mutant mouse models are valuable resources for the study of tendon and ligament biology. Many mutant mouse models are used because their manifested phenotypes mimic clinical pathobiology for several heritable disorders, such as Ehlers-Danlos Syndrome and Osteogenesis Imperfecta. Moreover, these models are helpful for discerning roles of specific genes in the development, maturation, and repair of musculoskeletal tissues. There are several categories of genes with essential roles in the synthesis and maintenance of tendon and ligament structures. The form and function of these tissues depend highly upon fibril-forming collagens, the primary extracellular macromolecules of tendons and ligaments. Models for these fibril-forming collagens, as well as for regulatory molecules like FACITs and SLRPs, are important for studying fibril assembly, growth, and maturation. Additionally, mouse models for growth factors and transcription factors are useful for defining regulation of cell proliferation, cell differentiation, and cues that stimulate matrix synthesis. Models for membrane-bound proteins assess the roles of cell-cell communication and cell-matrix interaction. In some cases, special considerations need to be given to spatio-temporal control of a gene in a model. Thus, conditional and inducible mouse models allow for specific regulation of genes of interest. Advances in mouse models have provided valuable tools for gaining insight into the form and function of tendons and ligaments.

  4. Aging, Breast Cancer and the Mouse Model

    DTIC Science & Technology

    2005-05-01

    Presenescent or senescent hBF (1.2 or 18x×10 4/well, respectively) [M, Stampfer , P. Yaswen, Lawrence Berkeley National Laboratory wdre suspended in 60 l cold...2.8 1 2.8 Inducing a human-like senescent phenotype in mouse fibroblasts Jean-Philihoo Copp , Simona Parrinello, Ana Krtolica, Christopher K. Patil...MAMMARY EPITHELIAL CELL PROLIFERATION AND TUMORIGENESIS: A MOUSE MODEL FOR HUMAN AGING. Jean-Philippe Coppe, Simona Parrinello, Ana Krtolica, Christopher

  5. Neurogenesis in mouse models of Alzheimer's disease.

    PubMed

    Chuang, Tsu Tshen

    2010-10-01

    The brains of the adult mouse and human possess neural stem cells (NSCs) that retain the capacity to generate new neurons through the process of neurogenesis. They share the same anatomical locations of stem cell niches in the brain, as well as the prominent feature of rostral migratory stream formed by neuroblasts migrating from the lateral ventricles towards the olfactory bulb. Therefore the mouse possesses some fundamental features that may qualify it as a relevant model for adult human neurogenesis. Adult born young hippocampal neurons in the mouse display the unique property of enhanced plasticity, and can integrate physically and functionally into existing neural circuits in the brain. Such crucial properties of neurogenesis may at least partially underlie the improved learning and memory functions observed in the mouse when hippocampal neurogenesis is augmented, leading to the suggestion that neurogenesis induction may be a novel therapeutic approach for diseases with cognitive impairments such as Alzheimer's disease (AD). Research towards this goal has benefited significantly from the use of AD mouse models to facilitate the understanding in the impact of AD pathology on neurogenesis. The present article reviews the growing body of controversial data on altered neurogenesis in mouse models of AD and attempts to assess their relative relevance to humans.

  6. Tetracycline-regulated mouse models of cancer.

    PubMed

    Yeh, Elizabeth S; Vernon-Grey, Ann; Martin, Heather; Chodosh, Lewis A

    2014-10-01

    Genetically engineered mouse models (GEMMs) have proven essential to the study of mammalian gene function in both development and disease. However, traditional constitutive transgenic mouse model systems are limited by the temporal and spatial characteristics of the experimental promoter used to drive transgene expression. To address this limitation, considerable effort has been dedicated to developing conditional and inducible mouse model systems. Although a number of approaches to generating inducible GEMMs have been pursued, several have been restricted by toxic or undesired physiological side effects of the compounds used to activate gene expression. The development of tetracycline (tet)-dependent regulatory systems has allowed for circumvention of these issues resulting in the widespread adoption of these systems as an invaluable tool for modeling the complex nature of cancer progression.

  7. A mouse model for too much TV?

    PubMed

    Bilimoria, Parizad M; Hensch, Takao K; Bavelier, Daphne

    2012-11-01

    In a new study published in Scientific Reports, Christakis and colleagues investigate a mouse model for technology-induced overstimulation. We review their findings, discuss the challenges of defining overstimulation, and consider the resemblance of the phenotypes observed in Christakis et al. to those noted in genetic models of attention deficit hyperactivity disorder (ADHD).

  8. Mouse models of the laminopathies

    SciTech Connect

    Stewart, Colin L. . E-mail: stewartc@ncifcrf.gov; Kozlov, Serguei; Fong, Loren G.; Young, Stephen G. . E-mail: sgyoung@mednet.ucla.edu

    2007-06-10

    The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

  9. Effects of verbenalin on prostatitis mouse model

    PubMed Central

    Miao, Mingsan; Guo, Lin; Yan, Xiaoli; Wang, Tan; Li, Zuming

    2015-01-01

    The aim of this study was to observe the treatment characteristics of verbenalin on a prostatitis mouse model. Give Xiaozhiling injection in the prostate locally to make a prostatitis mouse model. High, medium and low doses of verbenalin were each given to different mouse groups. The amount of water was determined in 14th, 28th. The number of white cells and lecithin corpuscle density in prostatic fluid were determined. Morphological changes in the prostate, testis, epididymis and kidney were detected. Compared with the model control group, the mice treated with high, medium and low doses of verbenalin had significantly increased amounts of water, and prostate white blood cell count and prostate volume density (Vv) were decreased significantly, the density of lecithin corpuscle score increased, and pathologic prostatitis changes were significantly reduced. Pathological change in the testis was significantly reduced and the change in the epididymis was obviously reduced. The thymic cortex thickness and the number of lymphocytes increased significantly and could reduce the renal pathological changes in potential. Verbenalin has a good therapeutic effect on the prostatitis mouse model. PMID:26858560

  10. Mouse Mammary Cancer Models - Mechanisms and Markers

    DTIC Science & Technology

    2001-08-01

    Wipl knockout mouse model and have shown defects in cell cycle control in cells derived from Wipl null animals. We are crossing these mice to mammary...compartment of the testes (13,14). Mice lacking Wipl are viable, but males show a reduced longevity and frequent runting (14). Wipl null males also show...predominates and thus the other TG/p53 mouse . Wnt-1 TG mice contain several copies nontumor components should not obscure any strong of a germline Wnt-1

  11. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.

    PubMed

    Stahl, Eli A; Wegmann, Daniel; Trynka, Gosia; Gutierrez-Achury, Javier; Do, Ron; Voight, Benjamin F; Kraft, Peter; Chen, Robert; Kallberg, Henrik J; Kurreeman, Fina A S; Kathiresan, Sekar; Wijmenga, Cisca; Gregersen, Peter K; Alfredsson, Lars; Siminovitch, Katherine A; Worthington, Jane; de Bakker, Paul I W; Raychaudhuri, Soumya; Plenge, Robert M

    2012-03-25

    The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.

  12. On Models and Mickey Mouse

    ERIC Educational Resources Information Center

    Petherbridge, Deanna

    2005-01-01

    The re-issue of a nineteenth-century French "Drawing Course" is the occasion for an examination of issues of "models of good practice" in current art teaching. These are listed as an expanded set of student-centred pedagogical paradigms, which embrace the forceful popular imagery of electronic games and comic strips. The formalist adaptations of…

  13. Mouse models of human disease

    PubMed Central

    Perlman, Robert L.

    2016-01-01

    The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans. PMID:27121451

  14. Mouse models for neural tube closure defects.

    PubMed

    Juriloff, D M; Harris, M J

    2000-04-12

    Neural tube closure defects (NTDs), in particular anencephaly and spina bifida, are common human birth defects (1 in 1000), their genetics is complex and their risk is reduced by periconceptional maternal folic acid supplementation. There are > 60 mouse mutants and strains with NTDs, many reported within the past 2 years. Not only are NTD mutations at loci widely heterogeneous in function, but also most of the mutants demonstrate variable low penetrance and some show complex inheritance patterns (e.g. SELH/Bc, Abl / Arg, Mena / Profilin1 ). In most of these mouse models, the NTDs are exencephaly (equivalent to anencephaly) or spina bifida or both, reflecting failure of neural fold elevation in well defined, mechanistically distinct elevation zones. NTD risk is reduced in various models by different maternal nutrient supplements, including folic acid ( Pax3, Cart1, Cd mutants), inositol ( ct ) and methionine ( Axd ). Lack of de novo methylation in embryos ( Dnmt3b -null) leads to NTD risk, and we suggest a potential link between methylation and the observed female excess among cranial NTDs in several models. Some surprising NTD mutants ( Gadd45a, Terc, Trp53 ) suggest that genes with a basic mitotic function also have a function specific to neural fold elevation. The genes mutated in several mouse NTD models involve actin regulation ( Abl/Arg, Macs, Mena/Profilin1, Mlp, Shrm, Vcl ), support the postulated key role of actin in neural fold elevation, and may be a good candidate pathway to search for human NTD genes.

  15. Interstitial Calcinosis in Renal Papillae of Genetically Engineered Mouse Models: Relation to Randall’s Plaques

    PubMed Central

    Wu, Xue-Ru

    2014-01-01

    Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na+-phosphate cotransporter Type II (Npt2a) and Na+/H+ exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall’s plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice are also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted in order to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and “compound mice” that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease. PMID:25096800

  16. Variability in Working Memory Performance Explained by Epistasis versus Polygenic Scores in the ZNF804A Pathway

    PubMed Central

    Morris, Derek; Anney, Richard; Gill, Michael; Corvin, Aiden; Donohoe, Gary

    2015-01-01

    Importance We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic score and epistatic analyses. Of particular importance was the relative contribution of the polygenic score versus epistasis in variation explained. Objective The objectives were twofold: first, to assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis. The second was to assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting and Participants Patients with psychosis (N = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention and social cognition. We used the Psychiatric GWAS Consortium (PGC1) schizophrenia GWAS to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (N = 170), which was used to develop linear regression models containing the polygenic score and two-SNP interactions. The best-fitting models were tested for replication in two independent test sets of cases: 1) 170 individuals with schizophrenia or schizoaffective disorder and 2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder and other psychosis). Results Higher polygenic scores were associated with poorer performance amongst patients on IQ, memory and social cognition, explaining 1-3% of variation on these scores (p-values ranged from 0.012-0.034). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and controls (N = 89) respectively, the

  17. Criteria for Validating Mouse Models of Psychiatric Diseases

    PubMed Central

    Chadman, Kathryn K.; Yang, Mu; Crawley, Jacqueline N.

    2010-01-01

    Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing the validity of a mouse model of a human brain dysfunction. We address the common question raised by molecular geneticists and clinical researchers in psychiatry, “what is a ‘good enough’ mouse model”? PMID:18484083

  18. Experimental photoallergic contact dermatitis: a mouse model

    SciTech Connect

    Maguire, H.C. Jr.; Kaidbey, K.

    1982-09-01

    We have induced photoallergic contact dermatitis in mice to 3,3',4',5 tetrachlorosalicylanilide (TCSA), chlorpromazine and 6-methylcoumarin. These compounds are known to produce photoallergic contact dermatitis in humans. The photoallergic contact dermatitis reaction in the mouse is immunologically specific viz. mice photosensitized to TCSA react, by photochallenge, to that compound and not to chlorpromazine, and conversely. The reaction requires UVA at both sensitization and challenge. It appears to be T-cell mediated in that it can be passively transferred to syngeneic mice by lymph node cells from actively sensitized mice, the histology of the reactions resembles that of classic allergic contact dermatitis in mice, challenge reactions are seen at 24 but not at 4 hr, and photoallergic contact dermatitis can be induced in B-cell deficient mice. The availability of a mouse model for the study of photo-ACD will facilitate the identification of pertinent control mechanisms and may aid in the management of the disease. It is likely that a bioassay for photoallergens of humans can be based on this mouse model.

  19. A Mouse Model for Osseous Heteroplasia

    PubMed Central

    Cheeseman, Michael T.; Vowell, Kate; Hough, Tertius A.; Jones, Lynn; Pathak, Paras; Tyrer, Hayley E.; Kelly, Michelle; Cox, Roger; Warren, Madhuri V.; Peters, Jo

    2012-01-01

    GNAS/Gnas encodes Gsα that is mainly biallelically expressed but shows imprinted expression in some tissues. In Albright Hereditary Osteodystrophy (AHO) heterozygous loss of function mutations of GNAS can result in ectopic ossification that tends to be superficial and attributable to haploinsufficiency of biallelically expressed Gsα. Oed-Sml is a point missense mutation in exon 6 of the orthologous mouse locus Gnas. We report here both the late onset ossification and occurrence of benign cutaneous fibroepithelial polyps in Oed-Sml. These phenotypes are seen on both maternal and paternal inheritance of the mutant allele and are therefore due to an effect on biallelically expressed Gsα. The ossification is confined to subcutaneous tissues and so resembles the ossification observed with AHO. Our mouse model is the first with both subcutaneous ossification and fibroepithelial polyps related to Gsα deficiency. It is also the first mouse model described with a clinically relevant phenotype associated with a point mutation in Gsα and may be useful in investigations of the mechanisms of heterotopic bone formation. Together with earlier results, our findings indicate that Gsα signalling pathways play a vital role in repressing ectopic bone formation. PMID:23284784

  20. Unstressing intemperate models: how cold stress undermines mouse modeling.

    PubMed

    Karp, Christopher L

    2012-06-04

    Mus musculus enjoys pride of place at the center of contemporary biomedical research. Despite being the current model system of choice for in vivo mechanistic analysis, mice have clear limitations. The literature is littered with examples of therapeutic approaches that showed promise in mouse models but failed in clinical trials. More generally, mice often provide poor mimics of the human diseases being modeled. Available data suggest that the cold stress to which laboratory mice are ubiquitously subjected profoundly affects mouse physiology in ways that impair the modeling of human homeostasis and disease. Experimental attention to this key, albeit largely ignored, environmental variable is likely to have a broad transformative effect on biomedical research.

  1. Mouse model of Staphylococcus aureus skin infection.

    PubMed

    Malachowa, Natalia; Kobayashi, Scott D; Braughton, Kevin R; DeLeo, Frank R

    2013-01-01

    Bacterial skin and soft tissue infections are abundant worldwide and many are caused by Staphylococcus aureus. Indeed, S. aureus is the leading cause of skin and soft tissue infections in the USA. Here, we describe a mouse model of skin and soft tissue infection induced by subcutaneous inoculation of S. aureus. This animal model can be used to investigate a number of factors related to the pathogenesis of skin and soft tissue infections, including strain virulence and the contribution of specific bacterial molecules to disease, and it can be employed to test the potential effectiveness of antibiotic therapies or vaccine candidates.

  2. Mouse Models of Anemia of Cancer

    PubMed Central

    Kim, Airie; Rivera, Seth; Shprung, Dana; Limbrick, Donald; Gabayan, Victoria; Nemeth, Elizabeta; Ganz, Tomas

    2014-01-01

    Anemia of cancer (AC) may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI), with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC. PMID:24681760

  3. Mouse models of intestinal inflammation and cancer.

    PubMed

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  4. Mouse Model of Coxiella burnetii Aerosolization

    PubMed Central

    Melenotte, Cléa; Lepidi, Hubert; Nappez, Claude; Bechah, Yassina; Audoly, Gilles; Terras, Jérôme; Raoult, Didier

    2016-01-01

    Coxiella burnetii is mainly transmitted by aerosols and is responsible for multiple-organ lesions. Animal models have shown C. burnetii pathogenicity, but long-term outcomes still need to be clarified. We used a whole-body aerosol inhalation exposure system to mimic the natural route of infection in immunocompetent (BALB/c) and severe combined immunodeficient (SCID) mice. After an initial lung inoculum of 104 C. burnetii cells/lung, the outcome, serological response, hematological disorders, and deep organ lesions were described up to 3 months postinfection. C. burnetii-specific PCR, anti-C. burnetii immunohistochemistry, and fluorescent in situ hybridization (FISH) targeting C. burnetii-specific 16S rRNA completed the detection of the bacterium in the tissues. In BALB/c mice, a thrombocytopenia and lymphopenia were first observed, prior to evidence of C. burnetii replication. In all SCID mouse organs, DNA copies increased to higher levels over time than in BALB/c ones. Clinical signs of discomfort appeared in SCID mice, so follow-up had to be shortened to 2 months in this group. At this stage, all animals presented bone, cervical, and heart lesions. The presence of C. burnetii could be attested in situ for all organs sampled using immunohistochemistry and FISH. This mouse model described C. burnetii Nine Mile strain spread using aerosolization in a way that corroborates the pathogenicity of Q fever described in humans and completes previously published data in mouse models. C. burnetii infection occurring after aerosolization in mice thus seems to be a useful tool to compare the pathogenicity of different strains of C. burnetii. PMID:27160294

  5. A mouse model of in utero transplantation.

    PubMed

    Nijagal, Amar; Le, Tom; Wegorzewska, Marta; Mackenzie, Tippi C

    2011-01-27

    The transplantation of stem cells and viruses in utero has tremendous potential for treating congenital disorders in the human fetus. For example, in utero transplantation (IUT) of hematopoietic stem cells has been used to successfully treat patients with severe combined immunodeficiency. In several other conditions, however, IUT has been attempted without success. Given these mixed results, the availability of an efficient non-human model to study the biological sequelae of stem cell transplantation and gene therapy is critical to advance this field. We and others have used the mouse model of IUT to study factors affecting successful engraftment of in utero transplanted hematopoietic stem cells in both wild-type mice and those with genetic diseases. The fetal environment also offers considerable advantages for the success of in utero gene therapy. For example, the delivery of adenoviral, adeno-associated viral, retroviral, and lentiviral vectors into the fetus has resulted in the transduction of multiple organs distant from the site of injection with long-term gene expression. in utero gene therapy may therefore be considered as a possible treatment strategy for single gene disorders such as muscular dystrophy or cystic fibrosis. Another potential advantage of IUT is the ability to induce immune tolerance to a specific antigen. As seen in mice with hemophilia, the introduction of Factor IX early in development results in tolerance to this protein. In addition to its use in investigating potential human therapies, the mouse model of IUT can be a powerful tool to study basic questions in developmental and stem cell biology. For example, one can deliver various small molecules to induce or inhibit specific gene expression at defined gestational stages and manipulate developmental pathways. The impact of these alterations can be assessed at various timepoints after the initial transplantation. Furthermore, one can transplant pluripotent or lineage specific progenitor

  6. A Mouse Model of Endocardial Fibroelastosis

    PubMed Central

    Clark, Elizabeth S.; Pepper, Victoria K.; Best, Cameron; Onwuka, Ekene; Yi, Tai; Tara, Shuhei; Cianciolo, Rachel; Baker, Peter; Shinoka, Toshiharu; Breuer, Christopher K.

    2015-01-01

    Background Endocardial Fibroelastosis (EFE) is a pathologic condition of abnormal deposition of collagen and elastin within the endocardium of the heart. It is seen in conjunction with a variety of diseases including hypoplastic left heart syndrome and viral endocarditis. While an experimental model using heterotopic heart transplant in rats has been described, we sought to fully describe a mouse model that can be used to further elucidate the potential mechanisms of and treatments for EFE. Materials and Methods The hearts of 2-day-old C57BL/6 mice were transplanted into the abdomen of 7-week-old C57BL/6 mice. At 2 weeks, the hearts were harvested and histologic analysis performed using hematoxylin and eosin, Masson’s Trichrome, Russell-Movat’s Pentachrome, Picrosirius Red, Hart’s, Verhoeff-Van Gieson, and Weigert’s Resorcin-Fuschin stains. Additionally, one heart was analysed using transmission electron microscopy (TEM). Results Specimens demonstrated abnormal accumulation of both collagen and elastin within the endocardium with occasional expansion in to the myocardium. Heterogeneity in extracellular matrix deposition was noted in the histologic specimens. In addition, TEM demonstrated the presence of excess collagen within the endocardium. Conclusions The heterotopic transplantation of an immature heart into a mouse results in changes consistent with EFE. This model is appropriate to investigate the etiology and treatment of endocardial fibroelastosis. PMID:26363814

  7. Mouse Genetic Models of Human Brain Disorders

    PubMed Central

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  8. Mouse models of otitis media: strengths and limitations.

    PubMed

    Bhutta, Mahmood Fazal

    2012-10-01

    There has been a rapid rise in the use of the mouse to investigate pathobiology of otitis media. This is for good reason, including easy husbandry, but also capacity for genetic manipulation of the mouse. Insights into human disease have been gleaned from mouse models, but there are limitations of the mouse-to-man approach. First, important differences exist between mouse and man, particularly in immune function. Second, functional equivalence of genes in the 2 species is not ensured. Third, laboratory mice of a uniform genetic background and environment are an inadequate model of the plethora of factors affecting complex disease in humans. Finally, gene function in mouse models is often obliterated using gene knockout technology, but this is a poor mimic of normal gene variation in man. These drawbacks of the mouse may in the future limit its usefulness in otitis media research.

  9. A humanoid mouse model of autism.

    PubMed

    Takumi, Toru

    2010-10-01

    Even now fruit of the human genome project is available, we have difficulties to approach neuropsychiatric disorders at the molecular level. Autism is a complex psychiatric illness but has received considerable attention as a developmental brain disorder not only from basic researchers but also from society. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We succeeded to generate mice with a 6.3-Mb-wide interstitial duplication in mouse chromosome 7c that is highly syntenic to human 15q11-13 by using a Cre-loxP-based chromosome-engineering technique. The only paternally duplicated mice display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit a developmental abnormality in ultrasonic vocalizations as well as anxiety. The detailed analysis focusing on a non-coding small nucleolar RNA, MBII52, within the duplicated region, revealed that the paternally duplicated mice alter the editing ratio of serotonin (5-HT) 2c receptor pre-mRNA and intracellular calcium responses by a 5-HT2c receptor specific agonist are changed in neurons. This result may explain one of molecular mechanisms of abnormal behaviors in the paternal duplicated mice. The first chromosome-engineered mouse model for human chromosome 15q11-13 duplication fulfills not only face validity of human autistic phenotypes but also construct validity based on human chromosome abnormality. This model will be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development.

  10. Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

    PubMed Central

    Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

    2015-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

  11. Genomic saturation mutagenesis and polygenic analysis identify novel yeast genes affecting ethyl acetate production, a non-selectable polygenic trait

    PubMed Central

    Abt, Tom Den; Souffriau, Ben; Foulquié-Moreno, Maria R.; Duitama, Jorge; Thevelein, Johan M.

    2016-01-01

    Isolation of mutants in populations of microorganisms has been a valuable tool in experimental genetics for decades. The main disadvantage, however, is the inability of isolating mutants in non-selectable polygenic traits. Most traits of organisms, however, are non-selectable and polygenic, including industrially important properties of microorganisms. The advent of powerful technologies for polygenic analysis of complex traits has allowed simultaneous identification of multiple causative mutations among many thousands of irrelevant mutations. We now show that this also applies to haploid strains of which the genome has been loaded with induced mutations so as to affect as many non-selectable, polygenic traits as possible. We have introduced about 900 mutations into single haploid yeast strains using multiple rounds of EMS mutagenesis, while maintaining the mating capacity required for genetic mapping. We screened the strains for defects in flavor production, an important non-selectable, polygenic trait in yeast alcoholic beverage production. A haploid strain with multiple induced mutations showing reduced ethyl acetate production in semi-anaerobic fermentation, was selected and the underlying quantitative trait loci (QTLs) were mapped using pooled-segregant whole-genome sequence analysis after crossing with an unrelated haploid strain. Reciprocal hemizygosity analysis and allele exchange identified PMA1 and CEM1 as causative mutant alleles and TPS1 as a causative genetic background allele. The case of CEM1 revealed that relevant mutations without observable effect in the haploid strain with multiple induced mutations (in this case due to defective mitochondria) can be identified by polygenic analysis as long as the mutations have an effect in part of the segregants (in this case those that regained fully functional mitochondria). Our results show that genomic saturation mutagenesis combined with complex trait polygenic analysis could be used successfully to

  12. Genomic saturation mutagenesis and polygenic analysis identify novel yeast genes affecting ethyl acetate production, a non-selectable polygenic trait.

    PubMed

    Abt, Tom Den; Souffriau, Ben; Foulquié-Moreno, Maria R; Duitama, Jorge; Thevelein, Johan M

    2016-03-18

    Isolation of mutants in populations of microorganisms has been a valuable tool in experimental genetics for decades. The main disadvantage, however, is the inability of isolating mutants in non-selectable polygenic traits. Most traits of organisms, however, are non-selectable and polygenic, including industrially important properties of microorganisms. The advent of powerful technologies for polygenic analysis of complex traits has allowed simultaneous identification of multiple causative mutations among many thousands of irrelevant mutations. We now show that this also applies to haploid strains of which the genome has been loaded with induced mutations so as to affect as many non-selectable, polygenic traits as possible. We have introduced about 900 mutations into single haploid yeast strains using multiple rounds of EMS mutagenesis, while maintaining the mating capacity required for genetic mapping. We screened the strains for defects in flavor production, an important non-selectable, polygenic trait in yeast alcoholic beverage production. A haploid strain with multiple induced mutations showing reduced ethyl acetate production in semi-anaerobic fermentation, was selected and the underlying quantitative trait loci (QTLs) were mapped using pooled-segregant whole-genome sequence analysis after crossing with an unrelated haploid strain. Reciprocal hemizygosity analysis and allele exchange identified PMA1 and CEM1 as causative mutant alleles and TPS1 as a causative genetic background allele. The case of CEM1 revealed that relevant mutations without observable effect in the haploid strain with multiple induced mutations (in this case due to defective mitochondria) can be identified by polygenic analysis as long as the mutations have an effect in part of the segregants (in this case those that regained fully functional mitochondria). Our results show that genomic saturation mutagenesis combined with complex trait polygenic analysis could be used successfully to

  13. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

    PubMed

    Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

    2015-01-01

    The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community.

  14. Mouse intragastric infusion (iG) model

    PubMed Central

    Ueno, Akiko; Lazaro, Raul; Wang, Ping-Yen; Higashiyama, Reiichi; Machida, Keigo; Tsukamoto, Hidekazu

    2014-01-01

    Direct intragastric delivery of a diet, nutrient or test substance can be achieved in rodents (mice and rats) on a long-term (2–3 months) basis using a chronically implanted gastrostomy catheter and a flow-through swivel system. This rodent intragastric infusion (iG) model has broad applications in research on food intake, gastrointestinal (GI) physiology, GI neuroendocrinology, drug metabolism and toxicity, obesity and liver disease. It achieves maximal control over the rate and pattern of delivery and it can be combined with normal ad libitum feeding of solid diet if so desired. It may be adopted to achieve infusion at other sites of the GI system to test the role of a bypassed GI segment in neuroendocrine physiology, and its use in genetic mouse models facilitates the genetic analysis of a central question under investigation. PMID:22461066

  15. Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia.

    PubMed

    Costas, J; Carrera, N; Alonso, P; Gurriarán, X; Segalàs, C; Real, E; López-Solà, C; Mas, S; Gassó, P; Domènech, L; Morell, M; Quintela, I; Lázaro, L; Menchón, J M; Estivill, X; Carracedo, Á

    2016-03-29

    Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10(-5)), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10(-6), explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications.

  16. Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia

    PubMed Central

    Costas, J; Carrera, N; Alonso, P; Gurriarán, X; Segalàs, C; Real, E; López-Solà, C; Mas, S; Gassó, P; Domènech, L; Morell, M; Quintela, I; Lázaro, L; Menchón, J M; Estivill, X; Carracedo, Á

    2016-01-01

    Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10−5), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10−6, explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications. PMID:27023174

  17. Genomic-polygenic evaluation of Angus-Brahman multibreed cattle for feed efficiency and postweaning growth using the Illumina 3K chip.

    PubMed

    Elzo, M A; Lamb, G C; Johnson, D D; Thomas, M G; Misztal, I; Rae, D O; Martinez, C A; Wasdin, J G; Driver, J D

    2012-08-01

    The objectives of this study were to determine the fraction of additive genetic variance explained by the SNP from the Illumina Bovine3K chip; to compare the ranking of animals evaluated with genomic-polygenic, genomic, and polygenic models; and to assess trends in predicted values from these 3 models for residual feed intake (RFI), daily feed intake (DFI), feed conversion ratio (FCR), and postweaning BW gain (PWG) in a multibreed Angus-Brahman cattle population under subtropical conditions. Data consisted of phenotypes and genotypes from 620 bulls, steers, and heifers ranging from 100% Angus to 100% Brahman. Phenotypes were collected in a GrowSafe automated feeding facility (GrowSafe Systems, Ltd., Airdrie, Alberta, Canada) from 2006 to 2010. Variance components were estimated using single-trait genomic-polygenic mixed models with option VCE (Markov chain Monte Carlo) of the program GS3. Fixed effects were contemporary group (year-pen), age of dam, sex of calf, age of calf, Brahman fraction of calf, and heterozygosity of calf. Random effects were additive SNP, animal polygenic, and residual effects. Genomic predictions were computed using a model without polygenic effects and polygenic predictions with a model that excluded additive SNP effects. Heritabilities were 0.20 for RFI, 0.31 for DFI, 0.21 for FCR, and 0.36 for PWG. The fraction of the additive genetic variance explained by SNP in the Illumina 3K chip was 15% for RFI, 11% for DFI, 25% for FCR, and 15% for PWG. These fractions will likely differ in other multibreed populations. Rank correlations between genomic-polygenic and polygenic predictions were high (0.95 to 0.99; P < 0.0001), whereas those between genomic-polygenic and genomic predictions were low (0.65 to 0.74; P < 0.0001). Genomic-polygenic, genomic, and polygenic predictions for all traits tended to decrease as Brahman fraction increased, indicating that calves with greater Brahman fraction were more efficient but grew more slowly than calves

  18. A mouse model of mandibular osteotomy healing.

    PubMed

    Paccione, M F; Warren, S M; Spector, J A; Greenwald, J A; Bouletreau, P J; Longaker, M T

    2001-09-01

    The purpose of this study was to establish a novel mouse model of membranous osteotomy healing. By applying this model to transgenic mice or using in situ hybridization techniques, we can subsequently investigate candidate genes that are believed to be important in membranous osteotomy healing. In the current study, 20 adult male CD-1 mice underwent a full-thickness osteotomy between the second and third molars of the right hemimandible using a 3-mm diamond disc and copious irrigation. Compo-Post pins were secured into the mandible, 2 mm anterior and posterior to the osteotomy. After the soft tissues were reapproximated and the skin was closed, an acrylic external fixator was attached to the exposed posts for stabilization. The animals were killed on postoperative day number 7, 10, 14, and 28 (n=5 animals per time point). The right hemimandibles were decalcified and embedded in paraffin for histologic evaluation or immunohistochemistry localizing osteocalcin. At 7 days after the osteotomy, early intramembranous bone formation could be seen extending from either edge of the osteotomized bone. By 10 days, an increasing number of small blood vessels could be seen within and around the osteotomy. At 14 days, the bone edges were in close approximation, and by 28 days the callus had been replaced by actively remodeling woven bone in all specimens examined. Immunohistochemistry demonstrated that osteocalcin expression correlated temporally with the transition from a soft to a hard callus. Furthermore, osteocalcin was spatially confined to osteoblasts actively laying down new osteoid or remodeling bone. This study describes a novel mouse model of membranous osteotomy healing that can be used as a paradigm for future osteotomy healing studies investigating candidate genes critical for osteogenesis and successful bone repair.

  19. Preclinical fluorescent mouse models of pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Bouvet, Michael; Hoffman, Robert M.

    2007-02-01

    Here we describe our cumulative experience with the development and preclinical application of several highly fluorescent, clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer. These models utilize the human pancreatic cancer cell lines which have been genetically engineered to selectively express high levels of the bioluminescent green fluorescent (GFP) or red fluorescent protein (RFP). Fluorescent tumors are established subcutaneously in nude mice, and tumor fragments are then surgically transplanted onto the pancreas. Locoregional tumor growth and distant metastasis of these orthotopic implants occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly specific, high-resolution, real-time visualization of tumor growth and metastasis may be achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. We have shown a high correlation between florescent optical imaging and magnetic resonance imaging in these models. Alternatively, transplantation of RFP-expressing tumor fragments onto the pancreas of GFP-expressing transgenic mice may be used to facilitate visualization of tumor-host interaction between the pancreatic tumor fragments and host-derived stroma and vasculature. Such in vivo models have enabled us to serially visualize and acquire images of the progression of pancreatic cancer in the live animal, and to demonstrate the real-time antitumor and antimetastatic effects of several novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate human pancreatic cancer and therapeutic strategies directed against it.

  20. Memory B cells in mouse models.

    PubMed

    Bergmann, B; Grimsholm, O; Thorarinsdottir, K; Ren, W; Jirholt, P; Gjertsson, I; Mårtensson, I-L

    2013-08-01

    One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases.

  1. A Transgenic Mouse Model of Poliomyelitis.

    PubMed

    Koike, Satoshi; Nagata, Noriyo

    2016-01-01

    Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model.

  2. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease

    PubMed Central

    Eppig, Janan T.; Blake, Judith A.; Bult, Carol J.; Kadin, James A.; Richardson, Joel E.

    2015-01-01

    The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse–human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human–Mouse: Disease Connection, allows users to explore gene–phenotype–disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. PMID:25348401

  3. Generation of gene-targeted mice using embryonic stem cells derived from a transgenic mouse model of Alzheimer's disease.

    PubMed

    Yamamoto, Satoshi; Ooshima, Yuki; Nakata, Mitsugu; Yano, Takashi; Matsuoka, Kunio; Watanabe, Sayuri; Maeda, Ryouta; Takahashi, Hideki; Takeyama, Michiyasu; Matsumoto, Yoshio; Hashimoto, Tadatoshi

    2013-06-01

    Gene-targeting technology using mouse embryonic stem (ES) cells has become the "gold standard" for analyzing gene functions and producing disease models. Recently, genetically modified mice with multiple mutations have increasingly been produced to study the interaction between proteins and polygenic diseases. However, introduction of an additional mutation into mice already harboring several mutations by conventional natural crossbreeding is an extremely time- and labor-intensive process. Moreover, to do so in mice with a complex genetic background, several years may be required if the genetic background is to be retained. Establishing ES cells from multiple-mutant mice, or disease-model mice with a complex genetic background, would offer a possible solution. Here, we report the establishment and characterization of novel ES cell lines from a mouse model of Alzheimer's disease (3xTg-AD mouse, Oddo et al. in Neuron 39:409-421, 2003) harboring 3 mutated genes (APPswe, TauP301L, and PS1M146V) and a complex genetic background. Thirty blastocysts were cultured and 15 stable ES cell lines (male: 11; female: 4) obtained. By injecting these ES cells into diploid or tetraploid blastocysts, we generated germline-competent chimeras. Subsequently, we confirmed that F1 mice derived from these animals showed similar biochemical and behavioral characteristics to the original 3xTg-AD mice. Furthermore, we introduced a gene-targeting vector into the ES cells and successfully obtained gene-targeted ES cells, which were then used to generate knockout mice for the targeted gene. These results suggest that the present methodology is effective for introducing an additional mutation into mice already harboring multiple mutated genes and/or a complex genetic background.

  4. Generation of transgenic mouse model using PTTG as an oncogene.

    PubMed

    Kakar, Sham S; Kakar, Cohin

    2015-01-01

    The close physiological similarity between the mouse and human has provided tools to understanding the biological function of particular genes in vivo by introduction or deletion of a gene of interest. Using a mouse as a model has provided a wealth of resources, knowledge, and technology, helping scientists to understand the biological functions, translocation, trafficking, and interaction of a candidate gene with other intracellular molecules, transcriptional regulation, posttranslational modification, and discovery of novel signaling pathways for a particular gene. Most importantly, the generation of the mouse model for a specific human disease has provided a powerful tool to understand the etiology of a disease and discovery of novel therapeutics. This chapter describes in detail the step-by-step generation of the transgenic mouse model, which can be helpful in guiding new investigators in developing successful models. For practical purposes, we will describe the generation of a mouse model using pituitary tumor transforming gene (PTTG) as the candidate gene of interest.

  5. Mouse models of colorectal cancer as preclinical models

    PubMed Central

    Buczacki, Simon J.A.; Arends, Mark J.; Adams, David J.

    2015-01-01

    In this review, we discuss the application of mouse models to the identification and pre‐clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large‐scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross‐species comparative ‘omics‐based approaches to this problem. We highlight recent progress in modelling late‐stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. PMID:26115037

  6. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer's disease: similarities to and differences from the transgenic model (3xTg-AD mouse).

    PubMed

    Chen, Yanxing; Liang, Zhihou; Blanchard, Julie; Dai, Chun-Ling; Sun, Shenggang; Lee, Moon H; Grundke-Iqbal, Inge; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2013-04-01

    Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

  7. Transgenic Mouse Model of Chronic Beryllium Disease

    SciTech Connect

    Gordon, Terry

    2009-05-26

    Animal models provide powerful tools for dissecting dose-response relationships and pathogenic mechanisms and for testing new treatment paradigms. Mechanistic research on beryllium exposure-disease relationships is severely limited by a general inability to develop a sufficient chronic beryllium disease animal model. Discovery of the Human Leukocyte Antigen (HLA) - DPB1Glu69 genetic susceptibility component of chronic beryllium disease permitted the addition of this human beryllium antigen presentation molecule to an animal genome which may permit development of a better animal model for chronic beryllium disease. Using FVB/N inbred mice, Drs. Rubin and Zhu, successfully produced three strains of HLA-DPB1 Glu 69 transgenic mice. Each mouse strain contains a haplotype of the HLA-DPB1 Glu 69 gene that confers a different magnitude of odds ratio (OR) of risk for chronic beryllium disease: HLA-DPB1*0401 (OR = 0.2), HLA-DPB1*0201 (OR = 15), HLA-DPB1*1701 (OR = 240). In addition, Drs. Rubin and Zhu developed transgenic mice with the human CD4 gene to permit better transmission of signals between T cells and antigen presenting cells. This project has maintained the colonies of these transgenic mice and tested the functionality of the human transgenes.

  8. Mouse infection models for space flight immunology

    NASA Technical Reports Server (NTRS)

    Chapes, Stephen Keith; Ganta, Roman Reddy; Chapers, S. K. (Principal Investigator)

    2005-01-01

    Several immunological processes can be affected by space flight. However, there is little evidence to suggest that flight-induced immunological deficits lead to illness. Therefore, one of our goals has been to define models to examine host resistance during space flight. Our working hypothesis is that space flight crews will come from a heterogeneous population; the immune response gene make-up will be quite varied. It is unknown how much the immune response gene variation contributes to the potential threat from infectious organisms, allergic responses or other long term health problems (e.g. cancer). This article details recent efforts of the Kansas State University gravitational immunology group to assess how population heterogeneity impacts host health, either in laboratory experimental situations and/or using the skeletal unloading model of space-flight stress. This paper details our use of several mouse strains with several different genotypes. In particular, mice with varying MHCII allotypes and mice on the C57BL background with different genetic defects have been particularly useful tools with which to study infections by Staphylococcus aureus, Salmonella typhimurium, Pasteurella pneumotropica and Ehrlichia chaffeensis. We propose that some of these experimental challenge models will be useful to assess the effects of space flight on host resistance to infection.

  9. Mouse models for gastric cancer: Matching models to biological questions

    PubMed Central

    Poh, Ashleigh R; O'Donoghue, Robert J J

    2016-01-01

    Abstract Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics. PMID:26809278

  10. Mouse Model of Halogenated Platinum Salt Hypersensitivity ...

    EPA Pesticide Factsheets

    Occupational exposure to halogenated platinum salts can trigger the development of asthma. Concern for increased asthma risk exists for the general population due to the use of platinum (Pt) in catalytic converters and its emerging use as a diesel fuel additive. To investigate airway responses to Pt, we developed a mouse model of Pt hypersensitivity. Previously, we confirmed the dermal sensitizing potency of ammonium hexachloroplatinate (AHCP) using an ex vivo [3H]methyl thymidine labeling version of the local lymph node assay in BALB/c mice. Here, we investigated the ability of AHCP to induce airway responses in mice sensitized by the dermal route. Mice were sensitized through application of 100 µL 1% AHCP in DMSO to the shaved back on days 0, 5 and 19, and 25 µl to each ear on days 10, 11 and 12. Unsensitized mice received vehicle. On day 24, mice were challenged by oropharyngeal aspiration (OPA) with 0 or 100 µg AHCP in saline. Before and immediately after challenge, airway responses were assessed using whole body plethysmography (WBP). On day 26, changes in ventilatory responses to methacholine (Mch) aerosol were assessed by WBP; dose-dependent increases in Mch responsiveness occurred in sensitized mice. Bronchoalveolar lavage fluid harvested from sensitized mice contained an average of 7.5% eosinophils compared to less than 0.5% in control mice (p < 0.05). This model will be useful for assessing both relative sensitizing potency and cross-reacti

  11. Mouse models for human hereditary deafness.

    PubMed

    Leibovici, Michel; Safieddine, Saaid; Petit, Christine

    2008-01-01

    Hearing impairment is a frequent condition in humans. Identification of the causative genes for the early onset forms of isolated deafness began 15 years ago and has been very fruitful. To date, approximately 50 causative genes have been identified. Yet, limited information regarding the underlying pathogenic mechanisms can be derived from hearing tests in deaf patients. This chapter describes the success of mouse models in the elucidation of some pathophysiological processes in the auditory sensory organ, the cochlea. These models have revealed a variety of defective structures and functions at the origin of deafness genetic forms. This is illustrated by three different examples: (1) the DFNB9 deafness form, a synaptopathy of the cochlear sensory cells where otoferlin is defective; (2) the Usher syndrome, in which deafness is related to abnormal development of the hair bundle, the mechanoreceptive structure of the sensory cells to sound; (3) the DFNB1 deafness form, which is the most common form of inherited deafness in Caucasian populations, mainly caused by connexin-26 defects that alter gap junction communication between nonsensory cochlear cells.

  12. Molecular approaches to human polygenic disease - Symposium 130

    SciTech Connect

    Not Available

    1987-01-01

    This volume deals with the application of recombinant DNA techniques to the identification of diseases that have more than one inherited component. Focus is on the polygenic factors responsible for coronary atherosclerosis. Several other disorders having a polygenic orgin are also discussed, including hypertension, diabetes mellitus, psychiatric diseases, and autoimmune (HLA-related) disorders. Problems raised by the study of different families or different populations are covered, as well as the possibility of applying molecular techniques to disease prevention-for example, through gene therapy. Also explored are some of the ethical issues that relate to human gene mapping.

  13. Mouse models of rhinovirus infection and airways disease.

    PubMed

    Bartlett, Nathan W; Singanayagam, Aran; Johnston, Sebastian L

    2015-01-01

    Mouse models are invaluable tools for gaining insight into host immunity during virus infection. Until recently, no practical mouse model for rhinovirus infection was available. Development of infection models was complicated by the existence of distinct groups of viruses that utilize different host cell surface proteins for binding and entry. Here, we describe mouse infection models, including virus purification and measurement of host immune responses, for representative viruses from two of these groups: (1) infection of unmodified Balb/c mice with minor group rhinovirus serotype 1B (RV-1B) and (2) infection of transgenic Balb/c mice with major group rhinovirus serotype 16 (RV-16).

  14. Mouse Models in Bone Marrow Transplantation and Adoptive Cellular Therapy

    PubMed Central

    Arber, Caroline; Brenner, Malcolm K.; Reddy, Pavan

    2014-01-01

    Mouse models of transplantation have been indispensable to the development of bone marrow transplantation (BMT). Their role in the generation of basic science knowledge is invaluable and is subject to discussion below. However, this article focuses on the direct role and relevance of mouse models towards the clinical development and advances in BMT and adoptive T-cell therapy for human diseases. The authors aim to present a thoughtful perspective on the pros and cons of mouse models while noting that despite imperfections these models are obligatory for the development of science-based medicine. PMID:24216170

  15. Development of a novel mouse constipation model

    PubMed Central

    Liang, Chao; Wang, Kai-Yue; Yu, Zhi; Xu, Bin

    2016-01-01

    AIM: To establish a novel mouse constipation model. METHODS: Animals were randomly divided into three groups, and intragastrically administered 0-4 °C saline (ice-cold group) or 15-20 °C saline (saline control group) daily for 14 d, or were left untreated (blank control group). Stools were collected 3-24 h after treatment to record the wet and dry weights and the stool form. Intestinal propulsion experiments were carried out and defecation time was measured for six days continuously after suspending treatments. The expressions of PGP9.5 were detected by immunohistochemistry. RESULTS: Based on the percentage of stool weight changes compared with baseline (before irritation) in 9-14 d, stool weight changes were classified into three levels. Each level shows a different body state, which is state I (no change: plus or minus 5%), state II (slightly decreased: 5%-15%) and state III (decreased: 15%-25%). In state III, between day 9-14, the stool weights decreased by 15%-25% compared with the baseline, and changed at a rate > 10% compared with blank control values, and the stools became small and dry. Additionally, intestinal functions degenerated in these animals, and PGP9.5-positive expression markedly decreased in jejunum, ileum and proximal colon myenteric plexus. CONCLUSION: Irritation with ice-cold saline is a stable, repeatable method in building constipation model in mice for exploring the pathogenesis and treatment options of constipation, and the change of stool weight and size may serve as a useful tool to judge a constipation model success or not. PMID:26973418

  16. A Mouse Model of Uterine Leiomyosarcoma

    PubMed Central

    Politi, Katerina; Szabolcs, Matthias; Fisher, Peter; Kljuic, Ana; Ludwig, Thomas; Efstratiadis, Argiris

    2004-01-01

    We are using an approach that is based on the cre/loxP recombination process and involves a binary system of Cre-producing and Cre-responding transgenic mice to achieve ubiquitous or tissue-specific expression of oncoproteins. To develop mouse models of tumorigenesis, Cre-producers are mated with responder animals carrying a dormant oncogene targeted into the 3′ untranslated region of the locus encoding cytoplasmic β-actin (actin cassette). Production of oncoprotein from a bicistronic message is accomplished in bitransgenic progeny by Cre-mediated excision of a segment flanked by loxP sites that is located upstream from the oncogenic sequence. Widespread Cre-dependent activation and expression of an actin-cassette transgene encoding the T antigens of the SV40 early region (SVER) commencing in embryos was compatible with normal development and did not impair viability. However, at ∼3 months of age, all female animals developed massive uterine leiomyosarcomas, whereas practically all males exhibited enormously enlarged seminal vesicles because of pronounced hyperplasia of the smooth muscle layers. In addition, because of smooth muscle hyperproliferation, marked dilation of the gallbladder was observed in mice of both sexes. To begin exploring aberrant signaling events in the SVER-triggered tumorigenic pathways, we analyzed the expression profile of leiomyosarcomas by DNA microarray analysis. PMID:14695345

  17. Mouse Models for Studying the Formation and Propagation of Prions*

    PubMed Central

    Watts, Joel C.; Prusiner, Stanley B.

    2014-01-01

    Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses. PMID:24860095

  18. Mouse Model of Human Hereditary Pancreatitis

    DTIC Science & Technology

    2016-09-01

    cause hereditary pancreatitis in humans. Previous attempts to introduce these mutant forms of human trypsinogen into mice have failed to produce...mutations in mouse trypsinogen isoform T7. Under this aim, we had two major tasks in our SOW: Major Task 1 was the design and construction of mutant forms...of the T7 mouse trypsinogen gene and expression and purification of these mutant enzymes. Major Task 2 was to analyze autoactivation of the T7

  19. Common variants at 30 loci contribute to polygenic dyslipidemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL)cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to ...

  20. Mouse Tumor Biology (MTB): a database of mouse models for human cancer.

    PubMed

    Bult, Carol J; Krupke, Debra M; Begley, Dale A; Richardson, Joel E; Neuhauser, Steven B; Sundberg, John P; Eppig, Janan T

    2015-01-01

    The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer-reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers.

  1. Whole-Genome Resequencing of Experimental Populations Reveals Polygenic Basis of Egg-Size Variation in Drosophila melanogaster.

    PubMed

    Jha, Aashish R; Miles, Cecelia M; Lippert, Nodia R; Brown, Christopher D; White, Kevin P; Kreitman, Martin

    2015-10-01

    Complete genome resequencing of populations holds great promise in deconstructing complex polygenic traits to elucidate molecular and developmental mechanisms of adaptation. Egg size is a classic adaptive trait in insects, birds, and other taxa, but its highly polygenic architecture has prevented high-resolution genetic analysis. We used replicated experimental evolution in Drosophila melanogaster and whole-genome sequencing to identify consistent signatures of polygenic egg-size adaptation. A generalized linear-mixed model revealed reproducible allele frequency differences between replicated experimental populations selected for large and small egg volumes at approximately 4,000 single nucleotide polymorphisms (SNPs). Several hundred distinct genomic regions contain clusters of these SNPs and have lower heterozygosity than the genomic background, consistent with selection acting on polymorphisms in these regions. These SNPs are also enriched among genes expressed in Drosophila ovaries and many of these genes have well-defined functions in Drosophila oogenesis. Additional genes regulating egg development, growth, and cell size show evidence of directional selection as genes regulating these biological processes are enriched for highly differentiated SNPs. Genetic crosses performed with a subset of candidate genes demonstrated that these genes influence egg size, at least in the large genetic background. These findings confirm the highly polygenic architecture of this adaptive trait, and suggest the involvement of many novel candidate genes in regulating egg size.

  2. Whole-Genome Resequencing of Experimental Populations Reveals Polygenic Basis of Egg-Size Variation in Drosophila melanogaster

    PubMed Central

    Jha, Aashish R.; Miles, Cecelia M.; Lippert, Nodia R.; Brown, Christopher D.; White, Kevin P.; Kreitman, Martin

    2015-01-01

    Complete genome resequencing of populations holds great promise in deconstructing complex polygenic traits to elucidate molecular and developmental mechanisms of adaptation. Egg size is a classic adaptive trait in insects, birds, and other taxa, but its highly polygenic architecture has prevented high-resolution genetic analysis. We used replicated experimental evolution in Drosophila melanogaster and whole-genome sequencing to identify consistent signatures of polygenic egg-size adaptation. A generalized linear-mixed model revealed reproducible allele frequency differences between replicated experimental populations selected for large and small egg volumes at approximately 4,000 single nucleotide polymorphisms (SNPs). Several hundred distinct genomic regions contain clusters of these SNPs and have lower heterozygosity than the genomic background, consistent with selection acting on polymorphisms in these regions. These SNPs are also enriched among genes expressed in Drosophila ovaries and many of these genes have well-defined functions in Drosophila oogenesis. Additional genes regulating egg development, growth, and cell size show evidence of directional selection as genes regulating these biological processes are enriched for highly differentiated SNPs. Genetic crosses performed with a subset of candidate genes demonstrated that these genes influence egg size, at least in the large genetic background. These findings confirm the highly polygenic architecture of this adaptive trait, and suggest the involvement of many novel candidate genes in regulating egg size. PMID:26044351

  3. M-cadherin, a candidate gene for type 2 diabetes and related phenotypes in a KK/Ta mouse model.

    PubMed

    Shiina, K; Gohda, T; Murakoshi, M; Yamada, K; Aoki, T; Yamazaki, T; Tanimoto, M; Tomino, Y

    2007-03-01

    The KK/Ta strain serves as a suitable polygenic mouse model for type 2 diabetes associated with fasting hyperglycaemia, glucose intolerance, hyperinsulinaemia, mild obesity and dyslipidaemia. Recently, we reported the susceptibility loci contributing to type 2 diabetes and related phenotypes in KK/Ta mice. In the present study, to identify susceptibility genes for type 2 diabetes and related disorders, GeneChip Expression Analysis was employed to survey the gene expression profile in the liver of KK/Ta and BALB/c mice. M-cadherin, a calciumdependent intercellular adhesion molecule, showed increased expression in the liver of KK/Ta mice, and sequence analysis revealed three missense mutations. The relationship between these polymorphisms and various phenotypes in 208 KK/Ta x (BALB/c x KK/Ta) F1 backcross mice was analysed. Statistical analysis revealed that M-cadherin exhibits linkage to levels of triglyceride and insulin in sera, glucose tolerance and body weight. Although it has been postulated that M-cadherin may be important for the regulation of morphogenesis of skeletal muscle cells, these results suggest that M-cadherin may influence hypertriglyceridaemia, glucose intolerance, hyperinsulinaemia and obesity in KK/Ta mice.

  4. Mouse Models to Study Dengue Virus Immunology and Pathogenesis

    PubMed Central

    Zellweger, Raphaël M.; Shresta, Sujan

    2014-01-01

    The development of a compelling murine model of dengue virus (DENV) infection has been challenging, because DENV clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows investigation of questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination) contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of anti-viral drugs or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV-infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies. PMID:24782859

  5. Mouse Genome Database: From sequence to phenotypes and disease models

    PubMed Central

    Richardson, Joel E.; Kadin, James A.; Smith, Cynthia L.; Blake, Judith A.; Bult, Carol J.

    2015-01-01

    Summary The Mouse Genome Database (MGD, www.informatics.jax.org) is the international scientific database for genetic, genomic, and biological data on the laboratory mouse to support the research requirements of the biomedical community. To accomplish this goal, MGD provides broad data coverage, serves as the authoritative standard for mouse nomenclature for genes, mutants, and strains, and curates and integrates many types of data from literature and electronic sources. Among the key data sets MGD supports are: the complete catalog of mouse genes and genome features, comparative homology data for mouse and vertebrate genes, the authoritative set of Gene Ontology (GO) annotations for mouse gene functions, a comprehensive catalog of mouse mutations and their phenotypes, and a curated compendium of mouse models of human diseases. Here, we describe the data acquisition process, specifics about MGD's key data areas, methods to access and query MGD data, and outreach and user help facilities. genesis 53:458–473, 2015. © 2015 The Authors. Genesis Published by Wiley Periodicals, Inc. PMID:26150326

  6. A Mouse Model of Chronic West Nile Virus Disease

    PubMed Central

    Graham, Jessica B.; Swarts, Jessica L.; Wilkins, Courtney; Thomas, Sunil; Green, Richard; Sekine, Aimee; Voss, Kathleen M.; Mooney, Michael; Choonoo, Gabrielle; Miller, Darla R.; Pardo Manuel de Villena, Fernando; Gale, Michael

    2016-01-01

    Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans. PMID:27806117

  7. System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

  8. The mouse model of respiratory syncytial virus disease.

    PubMed

    Openshaw, Peter J

    2013-01-01

    The laboratory mouse is the species of choice for most immunological studies, ranging from simple vaccine testing to the intricate dissection of fundamental immunopathogenic mechanisms. Although not fully mouse adapted, some strains of respiratory syncytial virus (RSV) replicate in the murine respiratory tract and induce specific T and B cell responses. Passive transfer of neutralising antibody is protective and assist in viral clearance. In addition, many of RSV's complex behaviours are recapitulated in the mouse (including enhancement of disease by vaccination and delayed effects of neonatal infection). However, human studies remain essential to confirm or refute predictions from animal models.

  9. Behavioral phenotypes of genetic mouse models of autism.

    PubMed

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

  10. Behavioral phenotypes of genetic mouse models of autism

    PubMed Central

    Kazdoba, T. M.; Leach, P. T.; Crawley, J. N.

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. PMID:26403076

  11. Development and testing of a mouse simulated space flight model

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1987-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occurs during space flight, and the carrying out of immunological experiments on animals undergoing space flight is examined. The mouse model developed was an antiorthostatic, hypokinetic, hypodynamic suspension model similar to one used with rats. The study was divided into two parts. The first involved determination of which immunological parameters should be observed on animals flown during space flight or studied in the suspension model. The second involved suspending mice and determining which of those immunological parameters were altered by the suspension. Rats that were actually flown in Space Shuttle SL-3 were used to test the hypotheses.

  12. Uterine disorders and pregnancy complications: insights from mouse models

    PubMed Central

    Lim, Hyunjung Jade; Wang, Haibin

    2010-01-01

    Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications. PMID:20364098

  13. Generation Of A Mouse Model For Schwannomatosis

    DTIC Science & Technology

    2010-09-01

    tumor virus (MMTV)-Cre, the whey acidic protein (WAP)-Cre, and the β-lactoglobulin (BLG)-Cre lines. We showed that merlin plays an important role...Cre lines, the mouse mammary tumor virus (MMTV)-Cre, the whey acidic protein (WAP)-Cre, and the β-lactoglobulin (BLG)-Cre lines. We showed that the...cycles, consequently leading to decreased milk production and malnourishment of the offspring by the second lactation. Immunostaining analysis revealed

  14. Finding Mouse Models of Human Lymphomas and Leukemia’s using The Jackson Laboratory Mouse Tumor Biology Database

    PubMed Central

    Begley, Dale A.; Sundberg, John P.; Krupke, Debra M.; Neuhauser, Steven B.; Bult, Carol J.; Eppig, Janan T.; Morse, Herbert C.; Ward, Jerrold M.

    2015-01-01

    Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. PMID:26302176

  15. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies

    PubMed Central

    Chatterjee, Nilanjan; Wheeler, Bill; Sampson, Joshua; Hartge, Patricia; Chanock, Stephen J.; Park, Ju-Hyun

    2013-01-01

    We report a new model to project the predictive performance of polygenic models based on the number and distribution of effect sizes for the underlying susceptibility alleles and the size of the training dataset. Using estimates of effect-size distribution and heritability derived from current studies, we project that while 45% of the variance of height has been attributed to common tagging Single Nucleotide Polymorphisms (SNP), a model trained on one million people may only explain 33.4% of variance of the trait. Current studies can identify 3.0%, 1.1%, and 7.0%, of the populations who are at two-fold or higher than average risk for Type 2 diabetes, coronary artery disease and prostate cancer, respectively. Tripling of sample sizes could elevate the percentages to 18.8%, 6.1%, and 12.2%, respectively. The utility of future polygenic models will depend on achievable sample sizes, underlying genetic architecture and information on other risk-factors, including family history. PMID:23455638

  16. The value of incomplete mouse models of Alzheimer's disease.

    PubMed

    Radde, Rebecca; Duma, Cecilia; Goedert, Michel; Jucker, Mathias

    2008-03-01

    To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Abeta42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral beta-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging.

  17. Mouse models for understanding human developmental anomalies

    SciTech Connect

    Generoso, W.M.

    1989-01-01

    The mouse experimental system presents an opportunity for studying the nature of the underlying mutagenic damage and the molecular pathogenesis of this class of anomalies by virtue of the accessibility of the zygote and its descendant blastomeres. Such studies could contribute to the understanding of the etiology of certain sporadic but common human malformations. The vulnerability of the zygotes to mutagens as demonstrated in the studies described in this report should be a major consideration in chemical safety evaluation. It raises questions regarding the danger to human zygotes when the mother is exposed to drugs and environmental chemicals.

  18. Mouse Model of Human Hereditary Pancreatitis

    DTIC Science & Technology

    2015-09-01

    trypsinogen cause hereditary pancreatitis in humans. Previous attempts to introduce these mutant forms of human trypsinogen into mice have failed to...cationic trypsinogen gene and obtained several new mutant strains. These newly created mouse strains will be characterized with respect to spontaneous...10 8. Special Reporting Requirements……………………………………11 9. Appendices……………………………………………………………11 4  Figure 1. Mutant forms of T7 trypsinogen

  19. Mouse models of primary Sjögren’s syndrome

    PubMed Central

    Park, Young-Seok; Gauna, Adrienne E.; Cha, Seunghee

    2015-01-01

    Sjögren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models. PMID:25777752

  20. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Cancer.gov

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  1. History and milestones of mouse models of autoimmune diseases.

    PubMed

    Yu, Xinhua; Huang, Qiaoniang; Petersen, Frank

    2015-01-01

    Autoimmune diseases are a group of disorders mediated by self-reactive T cells and/or autoantibodies. Mice, as the most widely used animal for modeling autoimmune disorders, have been extensively used in the investigation of disease pathogenesis as well as in the search for novel therapeutics. Since the first mouse model of multiple sclerosis was established more than 60 years ago, hundreds of mouse models have been established for tens of autoimmune diseases. These mouse models can be divided into three categories based on the approaches used for disease induction. The first one represents the induced models in which autoimmunity is initiated in mice by immunization, adoptive transfer or environmental factors. The second group is formed by the spontaneous models where mice develop autoimmune disorders without further induction. The third group refers to the humanized models in which mice bearing humanized cells, tissues, or genes, develop autoimmune diseases either spontaneously or by induction. This article reviews the history and highlights the milestones of the mouse models of autoimmune diseases.

  2. Mouse Models of Thyroid Cancer: A 2015 Update

    PubMed Central

    Kirschner, Lawrence S.; Qamri, Zahida; Kari, Suresh; Ashtekar, Amruta

    2015-01-01

    Thyroid cancer is the most common endocrine neoplasm, and its rate is rising at an alarming pace. Thus, there is a compelling need to develop in vivo models which will not only enable the confirmation of the oncogenic potential of driver genes, but also point the way towards the development of new therapeutics. Over the past 20 years, techniques for the generation of mouse models of human diseases have progressed substantially, accompanied by parallel advances in the genetics and genomics of human tumors. This convergence has enabled the development of mouse lines carrying mutations in the genes that cause thyroid cancers of all subtypes, including differentiated papillary and follicular thyroid cancers, poorly differentiated/anaplastic cancers, and medullary thyroid cancers. In this review, we will discuss the state of the art of mouse modeling of thyroid cancer, with the eventual goal of providing insight into tumor biology and treatment. PMID:26123589

  3. A mouse model of orthotopic vascularized aerated lung transplantation.

    PubMed

    Okazaki, M; Krupnick, A S; Kornfeld, C G; Lai, J M; Ritter, J H; Richardson, S B; Huang, H J; Das, N A; Patterson, G A; Gelman, A E; Kreisel, D

    2007-06-01

    Outcomes after lung transplantation are markedly inferior to those after other solid organ transplants. A better understanding of cellular and molecular mechanisms contributing to lung graft injury will be critical to improve outcomes. Advances in this field have been hampered by the lack of a mouse model of lung transplantation. Here, we report a mouse model of vascularized aerated single lung transplantation utilizing cuff techniques. We show that syngeneic grafts have normal histological appearance with minimal infiltration of T lymphocytes. Allogeneic grafts show acute cellular rejection with infiltration of T lymphocytes and recipient-type antigen presenting cells. Our data show that we have developed a physiological model of lung transplantation in the mouse, which provides ample opportunity for the study of nonimmune and immune mechanisms that contribute to lung allograft injury.

  4. Optimum polygenic profile to resist exertional rhabdomyolysis during a marathon

    PubMed Central

    Valero, Marjorie; Salinero, Juan José; Lara, Beatriz; Gallo-Salazar, César; Areces, Francisco

    2017-01-01

    Purpose Exertional rhabdomyolysis can occur in individuals performing various types of exercise but it is unclear why some individuals develop this condition while others do not. Previous investigations have determined the role of several single nucleotide polymorphisms (SNPs) to explain inter-individual variability of serum creatine kinase (CK) concentrations after exertional muscle damage. However, there has been no research about the interrelationship among these SNPs. The purpose of this investigation was to analyze seven SNPs that are candidates for explaining individual variations of CK response after a marathon competition (ACE = 287bp Ins/Del, ACTN3 = p.R577X, CKMM = NcoI, IGF2 = C13790G, IL6 = 174G>C, MLCK = C37885A, TNFα = 308G>A). Methods Using Williams and Folland’s model, we determined the total genotype score from the accumulated combination of these seven SNPs for marathoners with a low CK response (n = 36; serum CK <400 U·L-1) vs. marathoners with a high CK response (n = 31; serum CK ≥400 U·L-1). Results At the end of the race, low CK responders had lower serum CK (290±65 vs. 733±405 U·L-1; P<0.01) and myoglobin concentrations (443±328 vs. 1009±971 ng·mL-1, P<0.01) than high CK responders. Although the groups were similar in age, anthropometric characteristics, running experience and training habits, total genotype score was higher in low CK responders than in high CK responders (5.2±1.4 vs. 4.4±1.7 point, P = 0.02). Conclusion Marathoners with a lower CK response after the race had a more favorable polygenic profile than runners with high serum CK concentrations. This might suggest a significant role of genetic polymorphisms in the levels of exertional muscle damage and rhabdomyolysis. Yet other SNPs, in addition to exercise training, might also play a role in the values of CK after damaging exercise. PMID:28257486

  5. Polygenic eruptions on Alba Patera, Mars

    NASA Technical Reports Server (NTRS)

    Mouginis-Mark, P. J.; Wilson, L.; Zimbelman, J. R.

    1988-01-01

    A new model for the evolution of the martian volcano Alba Patera is constructed. Numerous digitate channel networks on the flanks of the volcano are interpreted to be carved by sapping due to the release of nonjuvenile water from unconsolidated flank deposits. The particle size of these deposits is estimated to be 3-10 microns, which, together with theoretical modelling of the disperison of explosively derived volcanic materials, leads to the conclusion that the flank deposits on Alba Patera are low-relief pyroclastic flows. The recognition of numerous late-stage summit and subterminal lava flows thus makes Alba Patera a unique martian volcano that is transitional between the older pyroclastic-dominated highland paterae and the more recent effusive central-vent volcanoes such as the Tharsis Montes.

  6. A polygenic hypothesis for sex determination in the European sea bass Dicentrarchus labrax.

    PubMed

    Vandeputte, Marc; Dupont-Nivet, Mathilde; Chavanne, Hervé; Chatain, Béatrice

    2007-06-01

    Polygenic sex determination, although suspected in several species, is thought to be evolutionarily unstable and has been proven in very few cases. In the European sea bass, temperature is known to influence the sex ratio. We set up a factorial mating, producing 5.893 individuals from 253 full-sib families, all reared in a single batch to avoid any between-families environmental effects. The proportion of females in the offspring was 18.3%, with a large variation between families. Interpreting sex as a threshold trait, the heritability estimate was 0.62 +/- 0.12. The observed distribution of family sex ratios was in accordance with a polygenic model or with a four-sex-factors system with environmental variance and could not be explained by any genetic model without environmental variance. We showed that there was a positive genetic correlation between weight and sex (r(A) = 0.50 +/- 0.09), apart from the phenotypic sex dimorphism in favor of females. This supports the hypothesis that a minimum size is required for sea bass juveniles to differentiate as females. An evolution of sex ratio by frequency-dependent selection is expected during the domestication process of Dicentrarchus labrax populations, raising concern about the release of such fish in the wild.

  7. A Mouse Model for Laser-induced Choroidal Neovascularization.

    PubMed

    Shah, Ronil S; Soetikno, Brian T; Lajko, Michelle; Fawzi, Amani A

    2015-12-27

    The mouse laser-induced choroidal neovascularization (CNV) model has been a crucial mainstay model for neovascular age-related macular degeneration (AMD) research. By administering targeted laser injury to the RPE and Bruch's membrane, the procedure induces angiogenesis, modeling the hallmark pathology observed in neovascular AMD. First developed in non-human primates, the laser-induced CNV model has come to be implemented into many other species, the most recent of which being the mouse. Mouse experiments are advantageously more cost-effective, experiments can be executed on a much faster timeline, and they allow the use of various transgenic models. The miniature size of the mouse eye, however, poses a particular challenge when performing the procedure. Manipulation of the eye to visualize the retina requires practice of fine dexterity skills as well as simultaneous hand-eye-foot coordination to operate the laser. However, once mastered, the model can be applied to study many aspects of neovascular AMD such as molecular mechanisms, the effect of genetic manipulations, and drug treatment effects. The laser-induced CNV model, though useful, is not a perfect model of the disease. The wild-type mouse eye is otherwise healthy, and the chorio-retinal environment does not mimic the pathologic changes in human AMD. Furthermore, injury-induced angiogenesis does not reflect the same pathways as angiogenesis occurring in an age-related and chronic disease state as in AMD. Despite its shortcomings, the laser-induced CNV model is one of the best methods currently available to study the debilitating pathology of neovascular AMD. Its implementation has led to a deeper understanding of the pathogenesis of AMD, as well as contributing to the development of many of the AMD therapies currently available.

  8. [Genetically engineered mice: mouse models for cancer research].

    PubMed

    Szymańska, Hanna

    2007-10-26

    Genetically engineered mice (GEM) have been extensively used to model human cancer. Mouse models mimic the morphology, histopathology, phenotype, and genotype of the corresponding cancer in humans. GEM mice are created by random integration of a transgene into the genome, which results in gene overexpression (transgenic mice); gene deletion (knock-out mice); or targeted insertion of the transgene in a selected locus (knock-in mice). Knock-out may be constitutive, i.e. total inactivation of the gene of interest in any cell, or conditional, i.e. tissue-specific inactivation of the gene. Gene knock-down (RNAi) and humanization of the mouse are more sophisticated models of GEM mice. RNA interference (RNAi) is a mechanism in which double-stranded RNAs inhibits the respective gene expression by inducing degradation of its mRNA. Humanization is based on replacing a mouse gene by its human counterpart. The alterations in genes in GEM have to be heritable. The opportunities provided by employing GEM cancer models are: analysis of the role of specific cancer genes and modifier genes, evaluation of conventional cancer therapies and new drugs, identification of cancer markers of tumor growth, analysis of the influence of the tumor's microenvironment on tumor formation, and the definition of the pre-clinical, discrete steps of tumorigenesis. The validation of mouse models of human cancer is the task of the MMHCC (Mouse Models of Human Cancer Consortium). The GEM models of breast, pancreatic, intestinal and colon, and prostate cancer are the most actively explored. In contrast, the models of brain tumors and ovary, cervical, and skin cancer are in the early stage of investigation.

  9. The clinical implications of mouse models of enhanced anxiety

    PubMed Central

    Sartori, Simone B; Landgraf, Rainer; Singewald, Nicolas

    2011-01-01

    Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applied in clinics remains challenging. One reason may be that most of the studies so far have used animals displaying ‘normal’ anxiety rather than ‘psychopathological’ animal models with abnormal (elevated) anxiety, which more closely reflect core features and sensitivities to therapeutic interventions of human anxiety disorders, and which would, thus, narrow the translational gap. Here, we discuss manipulations aimed at persistently enhancing anxiety-related behavior in the laboratory mouse using phenotypic selection, genetic techniques and/or environmental manipulations. It is hoped that such models with enhanced construct validity will provide improved ways of studying the neurobiology and treatment of pathological anxiety. Examples of findings from mouse models of enhanced anxiety-related behavior will be discussed, as well as their relation to findings in anxiety disorder patients regarding neuroanatomy, neurobiology, genetic involvement and epigenetic modifications. Finally, we highlight novel targets for potential anxiolytic pharmacotherapeutics that have been established with the help of research involving mice. Since the use of psychopathological mouse models is only just beginning to increase, it is still unclear as to the extent to which such approaches will enhance the success rate of drug development in translating identified therapeutic targets into clinical trials and, thus, helping to introduce the next anxiolytic class of drugs. PMID:21901080

  10. Inducible Mouse Models for Cancer Drug Target Validation

    PubMed Central

    Jeong, Joseph H.

    2016-01-01

    Genetically-engineered mouse (GEM) models have provided significant contributions to our understanding of cancer biology and developing anticancer therapeutic strategies. The development of GEM models that faithfully recapitulate histopathological and clinical features of human cancers is one of the most pressing needs to successfully conquer cancer. In particular, doxycycline-inducible transgenic mouse models allow us to regulate (induce or suppress) the expression of a specific gene of interest within a specific tissue in a temporal manner. Leveraging this mouse model system, we can determine whether the transgene expression is required for tumor maintenance, thereby validating the transgene product as a target for anticancer drug development (target validation study). In addition, there is always a risk of tumor recurrence with cancer therapy. By analyzing recurrent tumors derived from fully regressed tumors after turning off transgene expression in tumor-bearing mice, we can gain an insight into the molecular basis of how tumor cells escape from their dependence on the transgene (tumor recurrence study). Results from such studies will ultimately allow us to predict therapeutic responses in clinical settings and develop new therapeutic strategies against recurrent tumors. The aim of this review is to highlight the significance of doxycycline-inducible transgenic mouse models in studying target validation and tumor recurrence. PMID:28053958

  11. Development and testing of a mouse simulated space flight model

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1985-01-01

    The development and testing of a mouse model for simulating some aspects of weightlessness that occur during space flight, and the carrying out of immunological flight experiments on animals was discussed. The mouse model is an antiorthostatic, hypokinetic, hypodynamic suspension model similar to the one used with rats. It is shown that this murine model yield similar results to the rat model of antiorthostatic suspension for simulating some aspects of weightlessness. It is also shown that mice suspended in this model have decreased interferon-alpha/beta production as compared to control, nonsuspended mice or to orthostatically suspended mice. It is suggested that the conditions occuring during space flight could possibly affect interferon production. The regulatory role of interferon in nonviral diseases is demonstrated including several bacterial and protozoan infections indicating the great significance of interferon in resistance to many types of infectious diseases.

  12. Assessing the complex architecture of polygenic traits in diverged yeast populations.

    PubMed

    Cubillos, Francisco A; Billi, Eleonora; Zörgö, Enikö; Parts, Leopold; Fargier, Patrick; Omholt, Stig; Blomberg, Anders; Warringer, Jonas; Louis, Edward J; Liti, Gianni

    2011-04-01

    Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits.

  13. Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

    PubMed Central

    Proetzel, Gabriele; Wiles, Michael V.; Roopenian, Derry C.

    2015-01-01

    The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID:24150980

  14. Establishing the colitis-associated cancer progression mouse models.

    PubMed

    Zheng, Haiming; Lu, Zhanjun; Wang, Ruhua; Chen, Niwei; Zheng, Ping

    2016-12-01

    Inflammatory bowel disease (IBD) has been reported as an important inducer of colorectal cancer (CRC). The most malignant IBD-associated CRC type has been highlighted as colitis-associated cancer (CAC). However, lack of CAC cases and difficulties of the long follow-up research have challenged researchers in molecular mechanism probing. Here, we established pre-CAC mouse models (dextran sulfate sodium [DSS] group and azoxymethane [AOM] group) and CAC mouse model (DSS/AOM group) to mimic human CAC development through singly or combinational treatment with DSS and AOM followed by disease activity index analysis. We found that these CAC mice showed much more severe disease phenotype, including serious diarrhea, body weight loss, rectal prolapse and bleeding, bloody stool, tumor burden, and bad survival. By detecting expression patterns of several therapeutic targets-Apc, p53, Kras, and TNF-α-in these mouse models through western blot, histology analysis, qRT-PCR, and ELISA methods, we found that the oncogene Kras expression remained unchanged, while the tumor suppressors-Apc and p53 expression were both significantly downregulated with malignancy progression from pre-CAC to CAC, and TNF-α level was elevated the most in CAC mice blood which is of potential clinical use. These data indicated the successful establishment of CAC development mouse models, which mimics human CAC well both in disease phenotype and molecular level, and highlighted the promoting role of inflammation in CAC progression. This useful tool will facilitate the further study in CAC molecular mechanism.

  15. CHARACTERIZATION OF AEROMONAS VIRULENCE USING AN IMMUNOCOMPROMISED MOUSE MODEL

    EPA Science Inventory

    An immunocompromised mouse model was used to characterize Aeromonas strains for their ability to cause opportunistic, extraintestinal infections. A total of 34 isolates of Aeromonas (A. hydrophila [n = 12]), A. veronii biotype sobria [n = 7], A. caviae [n = 4], A. enchelia [n = 4...

  16. Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement

    PubMed Central

    Carey, Caitlin E.; Agrawal, Arpana; Bucholz, Kathleen K.; Hartz, Sarah M.; Lynskey, Michael T.; Nelson, Elliot C.; Bierut, Laura J.; Bogdan, Ryan

    2016-01-01

    Despite evidence of substantial comorbidity between psychiatric disorders and substance involvement, the extent to which common genetic factors contribute to their co-occurrence remains understudied. In the current study, we tested for associations between polygenic risk for psychiatric disorders and substance involvement (i.e., ranging from ever-use to severe dependence) among 2573 non-Hispanic European–American participants from the Study of Addiction: Genetics and Environment. Polygenic risk scores (PRS) for cross-disorder psychopathology (CROSS) were generated based on the Psychiatric Genomics Consortium’s Cross-Disorder meta-analysis and then tested for associations with a factor representing general liability to alcohol, cannabis, cocaine, nicotine, and opioid involvement (GENSUB). Follow-up analyses evaluated specific associations between each of the five psychiatric disorders which comprised CROSS—attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)—and involvement with each component substance included in GENSUB. CROSS PRS explained 1.10% of variance in GENSUB in our sample (p < 0.001). After correction for multiple testing in our follow-up analyses of polygenic risk for each individual disorder predicting involvement with each component substance, associations remained between: (A) MDD PRS and non-problem cannabis use, (B) MDD PRS and severe cocaine dependence, (C) SCZ PRS and non-problem cannabis use and severe cannabis dependence, and (D) SCZ PRS and severe cocaine dependence. These results suggest that shared covariance from common genetic variation contributes to psychiatric and substance involvement comorbidity. PMID:27574527

  17. Generation and Analysis of Humanized Mouse Model of EBV Infection.

    PubMed

    Imadome, Ken-Ichi; Fujiwara, Shigeyoshi

    2017-01-01

    The recent development of severely immunodeficient mouse strains enabled the production of new-generation humanized mice, in which major components of the human immune system are reconstituted. These new-generation humanized mice can be infected with human pathogenic viruses that do not infect regular mice and target cells of the hematoimmune system. Here we describe the method for preparing humanized mice, infecting them with EBV, and for their virological and immunological analyses. The results obtained from our own mouse models are briefly described.

  18. Retinal fundus imaging in mouse models of retinal diseases.

    PubMed

    Alex, Anne F; Heiduschka, Peter; Eter, Nicole

    2013-01-01

    The development of in vivo retinal fundus imaging in mice has opened a new research horizon, not only in ophthalmic research. The ability to monitor the dynamics of vascular and cellular changes in pathological conditions, such as neovascularization or degeneration, longitudinally without the need to sacrifice the mouse, permits longer observation periods in the same animal. With the application of the high-resolution confocal scanning laser ophthalmoscopy in experimental mouse models, access to a large spectrum of imaging modalities in vivo is provided.

  19. Modeling fragile X syndrome in the Fmr1 knockout mouse.

    PubMed

    Kazdoba, Tatiana M; Leach, Prescott T; Silverman, Jill L; Crawley, Jacqueline N

    2014-11-01

    Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.

  20. Current State of Animal (Mouse) Modeling in Melanoma Research

    PubMed Central

    Kuzu, Omer F.; Nguyen, Felix D.; Noory, Mohammad A.; Sharma, Arati

    2015-01-01

    Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future. PMID:26483610

  1. Comprehensive Neurocognitive Endophenotyping Strategies for Mouse Models of Genetic Disorders

    PubMed Central

    Hunsaker, Michael R.

    2012-01-01

    There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species. PMID:22266125

  2. Mouse models for studying prostate cancer bone metastasis

    PubMed Central

    Dai, Jinlu; Hensel, Janine; Wang, Ning; Kruithof-de Julio, Marianna; Shiozawa, Yusuke

    2016-01-01

    Once tumor cells metastasize to the bone, the prognosis for prostate cancer patients is generally very poor. The mechanisms involved in bone metastasis, however, remain elusive, because of lack of relevant animal models. In this manuscript, we describe step-by-step protocols for the xenograft mouse models that are currently used for studying prostate cancer bone metastasis. The different routes of tumor inoculation (intraosseous, intracardiac, intravenous and orthotopic) presented are useful for exploring the biology of bone metastasis. PMID:26916039

  3. Surgically-induced mouse models in the study of bone regeneration: Current models and future directions

    PubMed Central

    Ning, Bin; Zhao, Yunpeng; Buza, John A.; Li, Wei; Wang, Wenzhao; Jia, Tanghong

    2017-01-01

    Bone regeneration has been extensively studied over the past several decades. The surgically-induced mouse model is the key animal model for studying bone regeneration, of the various research strategies used. These mouse models mimic the trauma and recovery processes in vivo and serve as carriers for tissue engineering and gene modification to test various therapies or associated genes in bone regeneration. The present review introduces a classification of surgically induced mouse models in bone regeneration, evaluates the application and value of these models and discusses the potential development of further innovations in this field in the future. PMID:28138711

  4. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)

    PubMed Central

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-01-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence. PMID:27446562

  5. Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse).

    PubMed

    Takahashi, Tetsuyuki; Nishida, Takeshi; Baba, Hayato; Hatta, Hideki; Imura, Johji; Sutoh, Mitsuko; Toyohara, Syunji; Hokao, Ryoji; Watanabe, Syunsuke; Ogawa, Hirohisa; Uehara, Hisanori; Tsuneyama, Koichi

    2016-08-01

    We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.

  6. Practical use of advanced mouse models for lung cancer.

    PubMed

    Safari, Roghaiyeh; Meuwissen, Ralph

    2015-01-01

    To date a variety of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) mouse models have been developed that mimic human lung cancer. Chemically induced or spontaneous lung cancer in susceptible inbred strains has been widely used, but the more recent genetically engineered somatic mouse models recapitulate much better the genotype-phenotype correlations found in human lung cancer. Additionally, improved orthotopic transplantation of primary human cancer tissue fragments or cells into lungs of immune-compromised mice can be valuable tools for preclinical research such as antitumor drug tests. Here we give a short overview of most somatic mouse models for lung cancer that are currently in use. We accompany each different model with a description of its practical use and application for all major lung tumor types, as well as the intratracheal injection or direct injection of fresh or freeze-thawed tumor cells or tumor cell lines into lung parenchyma of recipient mice. All here presented somatic mouse models are based on the ability to (in) activate specific alleles at a time, and in a tissue-specific cell type, of choice. This spatial-temporal controlled induction of genetic lesions allows the selective introduction of main genetic lesions in an adult mouse lung as found in human lung cancer. The resulting conditional somatic mouse models can be used as versatile powerful tools in basic lung cancer research and preclinical translational studies alike. These distinctively advanced lung cancer models permit us to investigate initiation (cell of origin) and progression of lung cancer, along with response and resistance to drug therapy. Cre/lox or FLP/frt recombinase-mediated methods are now well-used techniques to develop tissue-restricted lung cancer in mice with tumor-suppressor gene and/or oncogene (in)activation. Intranasal or intratracheal administration of engineered adenovirus-Cre or lentivirus-Cre has been optimized for introducing Cre

  7. Common variants at 30 loci contribute to polygenic dyslipidemia

    PubMed Central

    Kathiresan, Sekar; Willer, Cristen J; Peloso, Gina; Demissie, Serkalem; Musunuru, Kiran; Schadt, Eric; Lee, Kaplan; Bennett, Derrick; Li, Yun; Tanaka, Toshiko; Voight, Benjamin F; Bonnycastle, Lori L; Jackson, Anne U; Crawford, Gabriel; Surti, Aarti; Guiducci, Candace; Burtt, Noel; Parish, Sarah; Clarke, Robert; Zelenika, Diana; Kubalanza, Kari A; Morken, Mario A; Scott, Laura J; Stringham, Heather M; Galan, Pilar; Swift, Amy J; Kuusisto, Johanna; Bergman, Richard N; Sundvall, Jouko; Laakso, Markku; Ferrucci, Luigi; Scheet, Paul; Sanna, Serena; Uda, Manuela; Yang, Qiong; Lunetta, Kathryn; Dupuis, Josee; deBakker, Paul I; O’Donnell, Christopher J; Chambers, John C; Kooner, Jaspal S; Hercberg, Serge; Meneton, Pierre; Lakatta, Edward G; Scuteri, Angelo; Schlessinger, David; Tuomilehto, Jaakko; Collins, Francis S; Groop, Leif; Altshuler, David; Collins, Rory; Lathrop, G Mark; Melander, Olle; Salomaa, Veikko; Peltonen, Leena; Orho-Melander, Marju; Ordovas, Jose M; Boehnke, Michael; Abecasis, Gonçalo R; Mohlke, Karen L; Cupples, L Adrienne

    2009-01-01

    Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 × 10-8), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10-15 for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia. PMID:19060906

  8. Spallanzani's mouse: a model of restoration and regeneration.

    PubMed

    Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

    2004-01-01

    The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

  9. Characterization of a Mouse Model of Hyperglycemia and Retinal Neovascularization

    PubMed Central

    Rakoczy, Elizabeth P.; Rahman, Ireni S. Ali; Binz, Nicolette; Li, Cai-Rui; Vagaja, Nermina N.; de Pinho, Marisa; Lai, Chooi-May

    2010-01-01

    One of the limitations of research into diabetic retinopathy is the lack of suitable animal models. To study how the two important factors—hyperglycemia and vascular endothelial growth factor—interact in diabetic retinopathy, the Akimba mouse (Ins2AkitaVEGF+/−) was generated by crossing the Akita mouse (Ins2Akita) with the Kimba mouse (VEGF+/+). C57Bl/6 and the parental and Akimba mouse lines were characterized by biometric measurements, histology, immunohistochemistry, and Spectralis Heidelberg retinal angiography and optical coherence tomography. The Akimba line not only retained the characteristics of the parental strains, such as developing hyperglycemia and retinal neovascularization, but developed higher blood glucose levels at a younger age and had worse kidney-body weight ratios than the Akita line. With aging, the Akimba line demonstrated enhanced photoreceptor cell loss, thinning of the retina, and more severe retinal vascular pathology, including more severe capillary nonperfusion, vessel constriction, beading, neovascularization, fibroses, and edema, compared with the Kimba line. The vascular changes were associated with major histocompatibility complex class II+ cellular staining throughout the retina. Together, these observations suggest that hyperglycemia resulted in higher prevalences of edema and exacerbated the vascular endothelial growth factor-driven neovascular and retinal changes in the Akimba line. Thus, the Akimba line could become a useful model for studying the interplay between hyperglycemia and vascular endothelial growth factor and for testing treatment strategies for potentially blinding complications, such as edema. PMID:20829433

  10. Oxidative Stress in Genetic Mouse Models of Parkinson's Disease

    PubMed Central

    Varçin, Mustafa; Bentea, Eduard; Michotte, Yvette; Sarre, Sophie

    2012-01-01

    There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, gene-environment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease. PMID:22829959

  11. Dissecting Alzheimer disease in Down syndrome using mouse models

    PubMed Central

    Choong, Xun Yu; Tosh, Justin L.; Pulford, Laura J.; Fisher, Elizabeth M. C.

    2015-01-01

    Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD. PMID:26528151

  12. Mouse models of ciliopathies: the state of the art.

    PubMed

    Norris, Dominic P; Grimes, Daniel T

    2012-05-01

    The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.

  13. Psoriasis: what we have learned from mouse models.

    PubMed

    Wagner, Erwin F; Schonthaler, Helia B; Guinea-Viniegra, Juan; Tschachler, Erwin

    2010-12-01

    Psoriasis is a common inflammatory skin disease of unknown etiology, for which there is no cure. This heterogeneous, cutaneous, inflammatory disorder is clinically characterized by prominent epidermal hyperplasia and a distinct inflammatory infiltrate. Crosstalk between immunocytes and keratinocytes, which results in the production of cytokines, chemokines and growth factors, is thought to mediate the disease. Given that psoriasis is only observed in humans, numerous genetic approaches to model the disease in mice have been undertaken. In this Review, we describe and critically assess the mouse models and transplantation experiments that have contributed to the discovery of novel disease-relevant pathways in psoriasis. Research performed using improved mouse models, combined with studies employing human cells, xenografts and patient material, will be key to our understanding of why such distinctive patterns of inflammation develop in patients with psoriasis. Indeed, a combination of genetic and immunological investigations will be necessary to develop both improved drugs for the treatment of psoriasis and novel curative strategies.

  14. Chemically induced mouse models of intestinal inflammation.

    PubMed

    Wirtz, Stefan; Neufert, Clemens; Weigmann, Benno; Neurath, Markus F

    2007-01-01

    Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans. Here, we provide protocols for establishing murine 2,4,6-trinitro benzene sulfonic acid (TNBS)-, oxazolone- and both acute and chronic dextran sodium sulfate (DSS) colitis, the most widely used chemically induced models of intestinal inflammation. In the former two models, colitis is induced by intrarectal administration of the covalently reactive reagents TNBS/oxazolone, which are believed to induce a T-cell-mediated response against hapten-modified autologous proteins/luminal antigens. In the DSS model, mice are subjected several days to drinking water supplemented with DSS, which seems to be directly toxic to colonic epithelial cells of the basal crypts. The procedures for the hapten models of colitis and acute DSS colitis can be accomplished in about 2 weeks but the protocol for chronic DSS colitis takes about 2 months.

  15. Behavioral phenotyping of mouse models of Parkinson's Disease

    PubMed Central

    Taylor, Tonya N.; Greene, James G.; Miller, Gary W.

    2010-01-01

    Parkinson's disease (PD) is a common neurodegenerative movement disorder afflicting millions of people in the United States. The advent of transgenic technologies has contributed to the development of several new mouse models, many of which recapitulate some aspects of the disease; however, no model has been demonstrated to faithfully reproduce the full constellation of symptoms seen in human PD. This may be due in part to the narrow focus on the dopamine-mediated motor deficits. As current research continues to unmask PD as a multi-system disorder, animal models should similarly evolve to include the non-motor features of the disease. This requires that typically cited behavioral test batteries be expanded. The major non-motor symptoms observed in PD patients include hyposmia, sleep disturbances, gastrointestinal dysfunction, autonomic dysfunction, anxiety, depression, and cognitive decline. Mouse behavioral tests exist for all of these symptoms and while some models have begun to be reassessed for the prevalence of this broader behavioral phenotype, the majority has not. Moreover, all behavioral paradigms should be tested for their responsiveness to L-DOPA so these data can be compared to patient response and help elucidate which symptoms are likely not dopamine-mediated. Here, we suggest an extensive, yet feasible, battery of behavioral tests for mouse models of PD aimed to better assess both non-motor and motor deficits associated with the disease. PMID:20211655

  16. Mouse models of multiple sclerosis: lost in translation?

    PubMed

    Baker, David; Amor, Sandra

    2015-01-01

    Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) leading to progressive accumulation of neurological deficits arising from recurrent episodes of inflammation, demyelination and neuronal degeneration. While the aetiology of the disease is unknown MS is widely considered to be the result of aberrant T cell and antibody responses to CNS antigens giving rise to the common concept that MS is an autoimmune disease or that there is an autoimmune component in the pathogenesis. This idea has lead to the development of experimental autoimmune encephalomyelitis (EAE) mouse models of MS in which immunisation with CNS antigens induces neurological and pathological signs of disease in mice. In addition to EAE models, injection with neurotropic viruses has been used to examine how infections are implicated in the disease process and how they may generate autoimmune responses in the CNS. Viral models are also crucial to investigate the impact of blocking trafficking of immune responses into the CNS since an emerging side-effect of current immunotherapeutic approaches in MS is the reactivation of viruses within the CNS. To investigate myelin damage and repair in the absence of the adaptive immune response, toxin-induced demyelination using cuprizone, ethidium bromide and lysolecithin, which rapidly leads to remyelination when the toxins are withdrawn, is also reviewed. Mice also lend themselves to the vast array of transgenic technologies to probe specific pathways as well as the use of humanised transgenic mice to examine the impact of human molecules. Despite the vast array of mouse models EAE is the most frequently exploited paradigm used to develop therapeutic approaches. However, despite over one thousand compounds used in the treatment of EAE few have become licenced for treatment of MS so far. Thus, this review also debates the reasons for these failures in mouse models as well as discusses how mouse models can be better utilised

  17. Mouse models and aging: longevity and progeria.

    PubMed

    Liao, Chen-Yu; Kennedy, Brian K

    2014-01-01

    Aging is a complex, multifactorial process that is likely influenced by the activities of a range of biological pathways. Genetic approaches to identify genes modulating longevity have been highly successful and recent efforts have extended these studies to mammalian aging. A variety of genetic models have been reported to have enhanced lifespan and, similarly, many genetic interventions lead to progeroid phenotypes. Here, we detail and evaluate both sets of models, focusing on the insights they provide about the molecular processes modulating aging and the extent to which mutations conferring progeroid pathologies really phenocopy accelerated aging.

  18. Association between polygenic risk for schizophrenia, neurocognition and social cognition across development

    PubMed Central

    Germine, L; Robinson, E B; Smoller, J W; Calkins, M E; Moore, T M; Hakonarson, H; Daly, M J; Lee, P H; Holmes, A J; Buckner, R L; Gur, R C; Gur, R E

    2016-01-01

    Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8–21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18–35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development. PMID:27754483

  19. Insights into mast cell functions in asthma using mouse models.

    PubMed

    Lei, Ying; Gregory, Joshua A; Nilsson, Gunnar P; Adner, Mikael

    2013-10-01

    Therapeutics targeting specific mechanisms of asthma have shown promising results in mouse models of asthma. However, these successes have not transferred well to the clinic or to the treatment of asthma sufferers. We suggest a reason for this incongruity is that mast cell-dependent responses, which may play an important role in the pathogenesis of both atopic and non-atopic asthma, are not a key component in most of the current asthma mouse models. Two reasons for this are that wild type mice have, in contrast to humans, a negligible number of mast cells localized in the smaller airways and in the parenchyma, and that only specific protocols show mast cell-dependent reactions. The development of mast cell-deficient mice and the reconstitution of mast cells within these mice have opened up the possibility to generate mouse models of asthma with a marked role of mast cells. In addition, mast cell-deficient mice engrafted with mast cells have a distribution of mast cells more similar to humans. In this article we review and highlight the mast cell-dependent and -independent responses with respect to airway hyperresponsiveness and inflammation in asthma models using mast cell-deficient and mast cell-engrafted mice.

  20. Nonspecific airway reactivity in a mouse model of asthma

    SciTech Connect

    Collie, D.D.; Wilder, J.A.; Bice, D.E.

    1995-12-01

    Animal models are indispensable for studies requiring an intact immune system, especially for studying the pathogenic mechanisms in atopic diseases, regulation of IgE production, and related biologic effects. Mice are particularly suitable and have been used extensively for such studies because their immune system is well characterized. Further, large numbers of mutants or inbred strains of mice are available that express deficiencies of individual immunologic processes, inflammatory cells, or mediator systems. By comparing reactions in such mice with appropriate control animals, the unique roles of individual cells or mediators may be characterized more precisely in the pathogenesis of atopic respiratory diseases including asthma. However, given that asthma in humans is characterized by the presence of airway hyperresponsiveness to specific and nonspecific stimuli, it is important that animal models of this disease exhibit similar physiologic abnormalities. In the past, the size of the mouse has limited its versatility in this regard. However, recent studies indicate the feasibility of measuring pulmonary responses in living mice, thus facilitating the physiologic evaluation of putative mouse models of human asthma that have been well charcterized at the immunologic and patholigic level. Future work will provide details of the morphometry of the methacholine-induced bronchoconstriction and will further seek to determine the relationship between cigarette smoke exposure and the development of NS-AHR in the transgenic mouse model.

  1. Novel robust hepatitis C virus mouse efficacy model.

    PubMed

    Zhu, Qing; Oei, Yoko; Mendel, Dirk B; Garrett, Evelyn N; Patawaran, Montesa B; Hollenbach, Paul W; Aukerman, Sharon L; Weiner, Amy J

    2006-10-01

    The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.

  2. Novel Robust Hepatitis C Virus Mouse Efficacy Model

    PubMed Central

    Zhu, Qing; Oei, Yoko; Mendel, Dirk B.; Garrett, Evelyn N.; Patawaran, Montesa B.; Hollenbach, Paul W.; Aukerman, Sharon L.; Weiner, Amy J.

    2006-01-01

    The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-α) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-α combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts. PMID:17005803

  3. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed Central

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  4. Mouse models for the study of colon carcinogenesis

    PubMed Central

    Rosenberg, Daniel W.; Giardina, Charles; Tanaka, Takuji

    2009-01-01

    The study of experimental colon carcinogenesis in rodents has a long history, dating back almost 80 years. There are many advantages to studying the pathogenesis of carcinogen-induced colon cancer in mouse models, including rapid and reproducible tumor induction and the recapitulation of the adenoma–carcinoma sequence that occurs in humans. The availability of recombinant inbred mouse panels and the existence of transgenic, knock-out and knock-in genetic models further increase the value of these studies. In this review, we discuss the general mechanisms of tumor initiation elicited by commonly used chemical carcinogens and how genetic background influences the extent of disease. We will also describe the general features of lesions formed in response to carcinogen treatment, including the underlying molecular aberrations and how these changes may relate to the pathogenesis of human colorectal cancer. PMID:19037092

  5. Mouse models of alphavirus-induced inflammatory disease.

    PubMed

    Taylor, Adam; Herrero, Lara J; Rudd, Penny A; Mahalingam, Suresh

    2015-02-01

    Part of the Togaviridae family, alphaviruses are arthropod-borne viruses that are widely distributed throughout the globe. Alphaviruses are able to infect a variety of vertebrate hosts, but in humans, infection can result in extensive morbidity and mortality. Symptomatic infection can manifest as fever, an erythematous rash and/or significant inflammatory pathologies such as arthritis and encephalitis. Recent overwhelming outbreaks of alphaviral disease have highlighted the void in our understanding of alphavirus pathogenesis and the re-emergence of alphaviruses has given new impetus to anti-alphaviral drug design. In this review, the development of viable mouse models of Old Word and New World alphaviruses is examined. How mouse models that best replicate human disease have been used to elucidate the immunopathology of alphavirus pathogenesis and trial novel therapeutic discoveries is also discussed.

  6. Magnolol inhibits the inflammatory response in mouse mammary epithelial cells and a mouse mastitis model.

    PubMed

    Wei, Wang; Dejie, Liang; Xiaojing, Song; Tiancheng, Wang; Yongguo, Cao; Zhengtao, Yang; Naisheng, Zhang

    2015-02-01

    Mastitis comprises an inflammation of the mammary gland, which is almost always linked with bacterial infection. The treatment of mastitis concerns antimicrobial substances, but not very successful. On the other hand, anti-inflammatory therapy with Chinese traditional medicine becomes an effective way for treating mastitis. Magnolol is a polyphenolic binaphthalene compound extracted from the stem bark of Magnolia sp., which has been shown to exert a potential for anti-inflammatory activity. The purpose of this study was to investigate the protective effects of magnolol on inflammation in lipopolysaccharide (LPS)-induced mastitis mouse model in vivo and the mechanism of this protective effects in LPS-stimulated mouse mammary epithelial cells (MMECs) in vitro. The damage of tissues was determined by histopathology and myeloperoxidase (MPO) assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Toll-like receptor 4 (TLR4) were determined by Western blot. The results showed that magnolol significantly inhibit the LPS-induced TNF-α, IL-6, and IL-1β production both in vivo and vitro. Magnolol declined the phosphorylation of IκBα, p65, p38, ERK, and JNK in LPS-stimulated MMECs. Furthermore, magnolol inhibited the expression of TLR4 in LPS-stimulated MMECs. In vivo study, it was also observed that magnolol attenuated the damage of mastitis tissues in the mouse models. These findings demonstrated that magnolol attenuate LPS-stimulated inflammatory response by suppressing TLR4/NF-κB/mitogen-activated protein kinase (MAPK) signaling system. Thereby, magnolol may be a therapeutic agent against mastitis.

  7. Polygenic risk of Parkinson disease is correlated with disease age at onset

    PubMed Central

    Escott‐Price, Valentina; Nalls, Mike A.; Morris, Huw R.; Lubbe, Steven; Brice, Alexis; Gasser, Thomas; Heutink, Peter; Wood, Nicholas W.; Hardy, John; Singleton, Andrew B.

    2015-01-01

    Objective We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset. Methods This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset. Results Our polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014). Interpretation This provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591 PMID:25773351

  8. Restoration of cone vision in a mouse model of achromatopsia.

    PubMed

    Alexander, John J; Umino, Yumiko; Everhart, Drew; Chang, Bo; Min, Seok H; Li, Qiuhong; Timmers, Adrian M; Hawes, Norman L; Pang, Ji-Jing; Barlow, Robert B; Hauswirth, William W

    2007-06-01

    Loss of cone function in the central retina is a pivotal event in the development of severe vision impairment for many prevalent blinding diseases. Complete achromatopsia is a genetic defect resulting in cone vision loss in 1 in 30,000 individuals. Using adeno-associated virus (AAV) gene therapy, we show that it is possible to target cones and rescue both the cone-mediated electroretinogram response and visual acuity in the Gnat2 ( cpfl3 ) mouse model of achromatopsia.

  9. POT of gold: modeling dyskeratosis congenita in the mouse

    PubMed Central

    Autexier, Chantal

    2008-01-01

    Dyskeratosis congenita (DC) is a rare syndrome, characterized by cutaneous abnormalities and premature death caused by bone marrow failure. In this issue of Genes & Development, Hockemeyer and colleagues (pp. 1773–1785) report a new mouse model that reconstitutes key features of DC. Disease phenotypes are generated by a POT1b deletion in a telomerase-deficient background that accelerates the shortening of telomeres by degradation. PMID:18593874

  10. Curcumin shows excellent therapeutic effect on psoriasis in mouse model.

    PubMed

    Kang, Di; Li, Bowen; Luo, Lei; Jiang, Wenbing; Lu, Qiumin; Rong, Mingqing; Lai, Ren

    2016-04-01

    Curcumin is an active herbal ingredient possessing surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. Recently, it has been reported to exhibit inhibitory activity on potassium channel subtype Kv1.3. As Kv1.3 channels are mainly expressed in T cells and play a key role in psoriasis, the effects of curcumin were investigated on inflammatory factors secretion in T cells and psoriasis developed in keratin (K) 14-vascular endothelial growth factor (VEGF) transgenic mouse model. Results showed that, 10 μM of curcumin significantly inhibited secretion of inflammatory factors including interleukin (IL)-17,IL-22, IFN-γ, IL-2, IL-8 and TNF-α in T cells by 30-60% in vitro. Notably, more than 50% of T cells proliferation was inhibited by application of 100 μM curcumin. Compared with severe psoriatic symptoms observed in the negative control mice, all psoriasis indexes including ear redness, weight, thickness and lymph node weight were significantly improved by oral application of curcumin in treatment mouse group. Histological examination indicated that curcumin had anti-inflammatory function in the experimental animals. More than 50% level of inflammatory factors including TNF-α, IFN-γ, IL-2, IL-12, IL-22 and IL-23 in mouse serum was decreased by curcumin treatment as well as cyclosporine. Compared with renal fibrosis observed in the mouse group treated by cyclosporine, no obvious side effect in mouse kidney was found after treated by curcumin. Taken together, curcumin, with high efficacy and safety, has a great potential to treat psoriasis.

  11. Behavioral Characterization of Mouse Models of Neuroferritinopathy

    PubMed Central

    Buffoli, Barbara; Rodella, Luigi F.; Cremona, Ottavio; Arosio, Paolo; Cirulli, Francesca

    2015-01-01

    Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing

  12. Genetically engineered mucin mouse models for inflammation and cancer

    PubMed Central

    Joshi, Suhasini; Kumar, Sushil; Bafna, Sangeeta; Rachagani, Satyanarayana; Wagner, Kay-Uwe; Jain, Maneesh

    2015-01-01

    Mucins are heavily O-glycosylated proteins primarily produced by glandular and ductal epithelial cells, either in membrane-tethered or secretory forms, for providing lubrication and protection from various exogenous and endogenous insults. However, recent studies have linked their aberrant overexpression with infection, inflammation, and cancer that underscores their importance in tissue homeostasis. In this review, we present current status of the existing mouse models that have been developed to gain insights into the functional role(s) of mucins under physiological and pathological conditions. Knockout mouse models for membrane-associated (Muc1 and Muc16) and secretory mucins (Muc2) have helped us to elucidate the role of mucins in providing effective and protective barrier functions against pathological threats, participation in disease progression, and improved our understanding of mucin interaction with biotic and abiotic environmental components. Emphasis is also given to available transgenic mouse models (MUC1 and MUC7), which has been exploited to understand the context-dependent regulation and therapeutic potential of human mucins during inflammation and cancer. PMID:25634251

  13. Mouse models of DNA mismatch repair in cancer research

    PubMed Central

    Lee, Kyeryoung; Tosti, Elena; Edelmann, Winfried

    2016-01-01

    Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies. PMID:26708047

  14. Mouse models of DNA mismatch repair in cancer research.

    PubMed

    Lee, Kyeryoung; Tosti, Elena; Edelmann, Winfried

    2016-02-01

    Germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) one of the most common cancer predisposition syndromes, and defects in MMR are also prevalent in sporadic colorectal cancers. In the past, the generation and analysis of mouse lines with knockout mutations in all of the known MMR genes has provided insight into how loss of individual MMR genes affects genome stability and contributes to cancer susceptibility. These studies also revealed essential functions for some of the MMR genes in B cell maturation and fertility. In this review, we will provide a brief overview of the cancer predisposition phenotypes of recently developed mouse models with targeted mutations in MutS and MutL homologs (Msh and Mlh, respectively) and their utility as preclinical models. The focus will be on mouse lines with conditional MMR mutations that have allowed more accurate modeling of human cancer syndromes in mice and that together with new technologies in gene targeting, hold great promise for the analysis of MMR-deficient intestinal tumors and other cancers which will drive the development of preventive and therapeutic treatment strategies.

  15. Mouse models: the ketogenic diet and polyunsaturated fatty acids.

    PubMed

    Borges, Karin

    2008-11-01

    Literature on the anticonvulsant effects of the ketogenic diet (KD) in mouse seizure models is summarized. Recent data show that a KD balanced in vitamin, mineral, and antioxidant content is anticonvulsant in mice, confirming that the KD's effect in mice can be attributed to the composition of the diet and not other dietary factors. Given that the anticonvulsant mechanism of the KD is still unknown, the anticonvulsant profile of the diet in different seizure models may help to decipher this mechanism. The implications of the findings that the KD is anticonvulsant in electrical seizure models are indicated. Further, the potential involvement of polyunsaturated fatty acids (PUFA) in the KD's anticonvulsant mechanism is discussed.

  16. Mouse models of dengue virus infection for vaccine testing.

    PubMed

    Sarathy, Vanessa V; Milligan, Gregg N; Bourne, Nigel; Barrett, Alan D T

    2015-12-10

    Dengue is a mosquito-borne disease caused by four serologically and genetically related viruses termed DENV-1 to DENV-4. With an annual global burden of approximately 390 million infections occurring in the tropics and subtropics worldwide, an effective vaccine to combat dengue is urgently needed. Historically, a major impediment to dengue research has been development of a suitable small animal infection model that mimics the features of human illness in the absence of neurologic disease that was the hallmark of earlier mouse models. Recent advances in immunocompromised murine infection models have resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice that are deficient in both the interferon-α/β receptor (IFN-α/β R) and the interferon-γ receptor (IFN-γR). These models mimic many hallmark features of dengue disease in humans, such as viremia, thrombocytopenia, vascular leakage, and cytokine storm. Importantly AG129 mice develop lethal, acute, disseminated infection with systemic viral loads, which is characteristic of typical dengue illness. Infected AG129 mice generate an antibody response to DENV, and antibody-dependent enhancement (ADE) models have been established by both passive and maternal transfer of DENV-immune sera. Several steps have been taken to refine DENV mouse models. Viruses generated by peripheral in vivo passages incur substitutions that provide a virulent phenotype using smaller inocula. Because IFN signaling has a major role in immunity to DENV, mice that generate a cellular immune response are desired, but striking the balance between susceptibility to DENV and intact immunity is complicated. Great strides have been made using single-deficient IFN-α/βR mice for DENV-2 infection, and conditional knockdowns may offer additional approaches to provide a panoramic view that includes viral virulence and host immunity. Ultimately, the DENV AG129 mouse models result in reproducible lethality and offer multiple

  17. Humanized mouse models of clinical disease

    PubMed Central

    Walsh, Nicole; Kenney, Laurie; Jangalwe, Sonal; Aryee, Ken-Edwin; Greiner, Dale L.; Brehm, Michael A.; Shultz, Leonard D.

    2017-01-01

    Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases. PMID:27959627

  18. EVALUATION OF AN IN VITRO TOXICOGENETIC MOUSE MODEL FOR HEPATOTOXICITY

    PubMed Central

    Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

    2010-01-01

    Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ, males) and cultured for up to 7 days in traditional 2-dimesional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver specific genes of hepatocytes isolated from different strains and cultured under standardized conditions is comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population. PMID:20869979

  19. Selective Blockade of Interferon-α and -β Reveals Their Non-Redundant Functions in a Mouse Model of West Nile Virus Infection

    PubMed Central

    Sheehan, Kathleen C. F.; Lazear, Helen M.; Diamond, Michael S.; Schreiber, Robert D.

    2015-01-01

    Although type I interferons (IFNs) were first described almost 60 years ago, the ability to monitor and modulate the functional activities of the individual IFN subtypes that comprise this family has been hindered by a lack of reagents. The major type I IFNs, IFN-β and the multiple subtypes of IFN-α, are expressed widely and induce their effects on cells by interacting with a shared heterodimeric receptor (IFNAR). In the mouse, the physiologic actions of IFN-α and IFN-β have been defined using polyclonal anti-type I IFN sera, by targeting IFNAR using monoclonal antibodies or knockout mice, or using Ifnb-/- mice. However, the corresponding analysis of IFN-α has been difficult because of its polygenic nature. Herein, we describe two monoclonal antibodies (mAbs) that differentially neutralize murine IFN-β or multiple subtypes of murine IFN-α. Using these mAbs, we distinguish specific contributions of IFN-β versus IFN-α in restricting viral pathogenesis and identify IFN-α as the key mediator of the antiviral response in mice infected with West Nile virus. This study thus suggests the utility of these new reagents in dissecting the antiviral and immunomodulatory roles of IFN-β versus IFN-α in murine models of infection, immunity, and autoimmunity. PMID:26010249

  20. ALIGNING MOUSE MODELS OF ASTHMA TO HUMAN ENDOTYPES OF DISEASE

    PubMed Central

    Martin, Rebecca A; Hodgkins, Samantha R; Dixon, Anne E; Poynter, Matthew E

    2014-01-01

    Substantial gains in understanding the pathophysiologic mechanisms underlying asthma have been made using preclinical mouse models. However, because asthma is a complex, heterogeneous syndrome that is rarely due to a single allergen and that often presents in the absence of atopy, few of the promising therapeutics that demonstrated effectiveness in mouse models have translated into new treatments for patients. This has resulted in an urgent need to characterize Th2-low, noneosinophilic subsets of asthma, to study models that are resistant to conventional treatments such as corticosteroids, and to develop therapies targeting patients with severe disease. Classifying asthma based on underlying pathophysiologic mechanisms, known as endotyping, offers a stratified approach for the development of new therapies for asthma. In preclinical research, new models of asthma are being utilized that more closely resemble the clinical features of different asthma endotypes, including the presence of IL-17 and a Th17 response, a biomarker of severe disease. These models utilize more physiologically relevant sensitizing agents, exacerbating factors, and allergens, as well as incorporate time points that better reflect the natural history and chronicity of clinical asthma. Importantly, some models better represent nonclassical asthma endotypes that facilitate the study of non-Th2 driven pathology and resemble the complex nature of clinical asthma, including corticosteroid resistance. Placing mouse asthma models into the context of human asthma endotypes will afford a more relevant approach to the understanding of pathophysiological mechanisms of disease that will afford the development of new therapies for those asthmatics that remain difficult to treat. PMID:24811131

  1. Mouse models of acute exacerbations of allergic asthma.

    PubMed

    Kumar, Rakesh K; Herbert, Cristan; Foster, Paul S

    2016-07-01

    Most of the healthcare costs associated with asthma relate to emergency department visits and hospitalizations because of acute exacerbations of underlying chronic disease. Development of appropriate animal models of acute exacerbations of asthma is a necessary prerequisite for understanding pathophysiological mechanisms and assessing potential novel therapeutic approaches. Most such models have been developed using mice. Relatively few mouse models attempt to simulate the acute-on-chronic disease that characterizes human asthma exacerbations. Instead, many reported models involve relatively short-term challenge with an antigen to which animals are sensitized, followed closely by an unrelated triggering agent, so are better described as models of potentiation of acute allergic inflammation. Triggers for experimental models of asthma exacerbations include (i) challenge with high levels of the sensitizing allergen (ii) infection by viruses or fungi, or challenge with components of these microorganisms (iii) exposure to environmental pollutants. In this review, we examine the strengths and weaknesses of published mouse models, their application for investigation of novel treatments and potential future developments.

  2. Revisiting the mouse model of oxygen-induced retinopathy

    PubMed Central

    Kim, Clifford B; D'Amore, Patricia A; Connor, Kip M

    2016-01-01

    Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR) has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress. PMID:27499653

  3. Mouse models for the Wolf-Hirschhorn deletion syndrome.

    PubMed

    Näf, D; Wilson, L A; Bergstrom, R A; Smith, R S; Goodwin, N C; Verkerk, A; van Ommen, G J; Ackerman, S L; Frankel, W N; Schimenti, J C

    2001-01-15

    Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.

  4. Vascularization of engineered cartilage constructs in a mouse model.

    PubMed

    Burghartz, Marc; Gehrke, Thomas; Storck, Katharina; Staudenmaier, Rainer; Mandlik, Veronika; Schurr, Christian; Hoang, Nguyen; Hagen, Rudolf; Kleinsasser, Norbert

    2015-02-01

    Tissue engineering of cartilage tissue offers a promising method for reconstructing ear, nose, larynx and trachea defects. However, a lack of sufficient nutrient supply to cartilage constructs limits this procedure. Only a few animal models exist to vascularize the seeded scaffolds. In this study, polycaprolactone (PCL)-based polyurethane scaffolds are seeded with 1 × 10(6) human cartilage cells and implanted in the right hind leg of a nude mouse using an arteriovenous flow-through vessel loop for angiogenesis for the first 3 weeks. Equally seeded scaffolds but without access to a vessel loop served as controls. After 3 weeks, a transposition of the vascularized scaffolds into the groin of the nude mouse was performed. Constructs (verum and controls) were explanted 1 and 6 weeks after transposition. Constructs with implanted vessels were well vascularized. The amount of cells increased in vascularized constructs compared to the controls but at the same time noticeably less extracellular matrix was produced. This mouse model provides critical answers to important questions concerning the vascularization of engineered tissue, which offers a viable option for repairing defects, especially when the desired amount of autologous cartilage or other tissues is not available and the nutritive situation at the implantation site is poor.

  5. Mouse Models of Follicular and Papillary Thyroid Cancer Progression

    PubMed Central

    Russo, Marika A.; Arciuch, Valeria G. Antico; Di Cristofano, Antonio

    2011-01-01

    A significant number of well-differentiated thyroid cancers progress or recur, becoming resistant to current therapeutic options. Mouse models recapitulating the genetic and histological features of advanced thyroid cancer have been an invaluable tool to dissect the mechanisms involved in the progression from indolent, well differentiated tumors to aggressive, poorly differentiated carcinomas, and to identify novel therapeutic targets. In this review, we focus on the lessons learned from models of epithelial cell-derived thyroid cancer showing progression from hyperplastic lesions to locally invasive and metastatic carcinomas. PMID:22654848

  6. Mouse models for studies of retinal degeneration and diseases

    PubMed Central

    Chang, Bo

    2013-01-01

    Summary Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human retinal degeneration. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Here, I describe the tools used in the discoveries of many retinal degeneration models, including indirect ophthalmoscopy (to look at the fundus appearance), fundus photography and fluorescein angiography (to document the fundus appearance), electroretinography (to check retinal function) as well as the heritability test (for genetic characterization). PMID:23150358

  7. Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

    PubMed Central

    Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

    2015-01-01

    Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

  8. Transgenic mouse model for the fragile X syndrome

    SciTech Connect

    Kooy, R.F.; Reyniers, E.; De Boulle, K.

    1996-08-09

    Transgenic fragile X knockout mice have been constructed to provide an animal model to study the physiologic function of the fragile X gene (FMR1) and to gain more insight into the clinical phenotype caused by the absence of the fragile X protein. Initial experiments suggested that the knockout mice show macroorchidism and cognitive and behavioral deficits, abnormalities comparable to those of human fragile X patients. In the present study, we have extended our experiments, and conclude that the Fmr1 knockout mouse is a reliable transgenic model to study the fragile X syndrome. 20 refs., 2 figs., 1 tab.

  9. Efficacy of cabazitaxel in mouse models of pediatric brain tumors

    PubMed Central

    Girard, Emily; Ditzler, Sally; Lee, Donghoon; Richards, Andrew; Yagle, Kevin; Park, Joshua; Eslamy, Hedieh; Bobilev, Dmitri; Vrignaud, Patricia; Olson, James

    2015-01-01

    Background There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors. Methods The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model. Results This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel. Conclusion These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors. PMID:25140037

  10. Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis

    PubMed Central

    Pashayan, Nora; Duffy, Stephen W.; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Martin, Richard M.; Harrington, Patricia; Benlloch, Sara; Amin Al Olama, Ali; Shah, Mitul; Kote-Jarai, Zsofia; Easton, Douglas F.; Eeles, Rosalind; Pharoah, Paul D.

    2015-01-01

    Purpose: This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk. Genet Med 17 10, 789–795. Methods: We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50–69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis. Genet Med 17 10, 789–795. Results: Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles. Genet Med 17 10, 789–795. Conclusion: Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer. Genet Med 17 10, 789–795. PMID:25569441

  11. Immunotherapeutic approaches for Alzheimer's disease in transgenic mouse models.

    PubMed

    Wisniewski, Thomas; Boutajangout, Allal

    2010-03-01

    Alzheimer's disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans.

  12. An Anisotropic Fluid-Solid Model of the Mouse Heart

    SciTech Connect

    Carson, James P.; Kuprat, Andrew P.; Jiao, Xiangmin; del Pin, Facundo; Einstein, Daniel R.

    2010-01-01

    A critical challenge in biomechanical simulations is the spatial discretization of complex fluid-solid geometries created from imaging. This is especially important when dealing with Lagrangian interfaces, as there must be at a minimum both geometric and topological compatibility between fluid and solid phases, with exact matching of the interfacial nodes being highly desirable. We have developed a solution to this problem and applied the approach to the creation of a 3D fluidsolid mesh of the mouse heart. First, a 50 micron isotropic MRI dataset of a perfusion-fixed mouse heart was segmented into blood, tissue, and background using a customized multimaterial connected fuzzy thresholding algorithm. Then, a multimaterial marching cubes algorithm was applied to produce two compatible isosurfaces, one for the blood-tissue boundary and one for the tissue-background boundary. A multimaterial smoothing algorithm that rigorously conserves volume for each phase simultaneously smoothed the isosurfaces. Next we applied novel automated meshing algorithms to generate anisotropic hybrid meshes with the number of layers and the desired element anisotropy for each material as the only input parameters. As the meshes are scale-invariant within a material and include boundary layer prisms, fluid-structure interaction computations would have a relative error equilibrated over the entire mesh. The resulting model is highly detailed mesh representation of the mouse heart, including features such as chordae and coronary vasculature, that is also maximally efficient to produce the best simulation results for the computational resources available

  13. Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, M; Adachi, H; Inukai, A; Sobue, G

    2003-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

  14. Venous Thrombosis and Cancer: from Mouse Models to Clinical Trials

    PubMed Central

    Hisada, Y.; Geddings, J. E.; Ay, C.; Mackman, N.

    2015-01-01

    Cancer patients have a ~4 fold increased risk of venous thromboembolism (VTE) compared with the general population and this is associated with significant morbidity and mortality. This review summarizes our current knowledge of VTE and cancer from mouse models to clinical studies. Notably, risk of VTE varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of VTE than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors and growth factors may directly and indirectly enhance VTE. For example, increased levels of circulating tumor-derived, tissue factor-positive microvesicles may trigger VTE. In a mouse model of ovarian cancer, tumor-derived IL-6 and hepatic thrombopoietin has been linked to increased platelet production and thrombosis. In addition, mouse models of mammary and lung cancer showed that tumor-derived granulocyte colony-stimulating factor causes neutrophilia and activation of neutrophils. Activated neutrophils can release neutrophil extracellular traps (NETs) that enhance thrombosis. Cell-free DNA in the blood derived from cancer cells, NETs and treatment with cytotoxic drugs can activate the clotting cascade. These studies suggest that there are multiple mechanisms for VTE in patients with different types of cancer. Preventing and treating VTE in cancer patients is challenging; the current recommendations are to use low molecular weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent VTE in cancer patients. PMID:25988873

  15. A STAT-1 knockout mouse model for Machupo virus pathogenesis

    PubMed Central

    2011-01-01

    Background Machupo virus (MACV), a member of the Arenaviridae, causes Bolivian hemorrhagic fever, with ~20% lethality in humans. The pathogenesis of MACV infection is poorly understood, and there are no clinically proven treatments for disease. This is due, in part, to a paucity of small animal models for MACV infection in which to discover and explore candidate therapeutics. Methods Mice lacking signal transducer and activator of transcription 1 (STAT-1) were infected with MACV. Lethality, viral replication, metabolic changes, hematology, histopathology, and systemic cytokine expression were analyzed throughout the course of infection. Results We report here that STAT-1 knockout mice succumbed to MACV infection within 7-8 days, and presented some relevant clinical and histopathological manifestations of disease. Furthermore, the model was used to validate the efficacy of ribavirin in protection against infection. Conclusions The STAT-1 knockout mouse model can be a useful small animal model for drug testing and preliminary immunological analysis of lethal MACV infection. PMID:21672221

  16. Mouse models for the discovery of colorectal cancer driver genes

    PubMed Central

    Clark, Christopher R; Starr, Timothy K

    2016-01-01

    Colorectal cancer (CRC) constitutes a major public health problem as the third most commonly diagnosed and third most lethal malignancy worldwide. The prevalence and the physical accessibility to colorectal tumors have made CRC an ideal model for the study of tumor genetics. Early research efforts using patient derived CRC samples led to the discovery of several highly penetrant mutations (e.g., APC, KRAS, MMR genes) in both hereditary and sporadic CRC tumors. This knowledge has enabled researchers to develop genetically engineered and chemically induced tumor models of CRC, both of which have had a substantial impact on our understanding of the molecular basis of CRC. Despite these advances, the morbidity and mortality of CRC remains a cause for concern and highlight the need to uncover novel genetic drivers of CRC. This review focuses on mouse models of CRC with particular emphasis on a newly developed cancer gene discovery tool, the Sleeping Beauty transposon-based mutagenesis model of CRC. PMID:26811627

  17. Mouse models for the discovery of colorectal cancer driver genes.

    PubMed

    Clark, Christopher R; Starr, Timothy K

    2016-01-14

    Colorectal cancer (CRC) constitutes a major public health problem as the third most commonly diagnosed and third most lethal malignancy worldwide. The prevalence and the physical accessibility to colorectal tumors have made CRC an ideal model for the study of tumor genetics. Early research efforts using patient derived CRC samples led to the discovery of several highly penetrant mutations (e.g., APC, KRAS, MMR genes) in both hereditary and sporadic CRC tumors. This knowledge has enabled researchers to develop genetically engineered and chemically induced tumor models of CRC, both of which have had a substantial impact on our understanding of the molecular basis of CRC. Despite these advances, the morbidity and mortality of CRC remains a cause for concern and highlight the need to uncover novel genetic drivers of CRC. This review focuses on mouse models of CRC with particular emphasis on a newly developed cancer gene discovery tool, the Sleeping Beauty transposon-based mutagenesis model of CRC.

  18. Mouse Models of Prostate Cancer: Picking the Best Model for the Question

    PubMed Central

    Grabowska, Magdalena M.; DeGraff, David J.; Yu, Xiuping; Jin, Ren Jie; Chen, Zhenbang; Borowsky, Alexander D.; Matusik, Robert J.

    2014-01-01

    When the NIH Mouse Models of Human Cancer Consortium (MMCC) initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for “prostate cancer mouse model” yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin (PB) promoter driving viral oncogenes such as SV40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and over-expression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question? PMID:24452759

  19. Mouse models of human AML accurately predict chemotherapy response

    PubMed Central

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S.; Zhao, Zhen; Rappaport, Amy R.; Luo, Weijun; McCurrach, Mila E.; Yang, Miao-Miao; Dolan, M. Eileen; Kogan, Scott C.; Downing, James R.; Lowe, Scott W.

    2009-01-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients. PMID:19339691

  20. Mouse models of human AML accurately predict chemotherapy response.

    PubMed

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S; Zhao, Zhen; Rappaport, Amy R; Luo, Weijun; McCurrach, Mila E; Yang, Miao-Miao; Dolan, M Eileen; Kogan, Scott C; Downing, James R; Lowe, Scott W

    2009-04-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients.

  1. Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy

    PubMed Central

    Saito, Takeyuki; Yokota, Kazuya; Kobayakawa, Kazu; Hara, Masamitsu; Kubota, Kensuke; Harimaya, Katsumi; Kawaguchi, Kenichi; Hayashida, Mitsumasa; Matsumoto, Yoshihiro; Doi, Toshio; Shiba, Keiichiro; Nakashima, Yasuharu; Okada, Seiji

    2017-01-01

    Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production. PMID:28060908

  2. Genetic mouse models of brain ageing and Alzheimer's disease.

    PubMed

    Bilkei-Gorzo, Andras

    2014-05-01

    Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed.

  3. Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics.

    PubMed

    Kazdoba, Tatiana M; Leach, Prescott T; Yang, Mu; Silverman, Jill L; Solomon, Marjorie; Crawley, Jacqueline N

    Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism.

  4. New Mouse Model for Dengue Virus Vaccine Testing

    PubMed Central

    Johnson, Alison J.; Roehrig, John T.

    1999-01-01

    Several dengue (DEN) virus vaccines are in development; however, the lack of a reliable small animal model in which to test them is a major obstacle. Because evidence suggests that interferon (IFN) is involved in the human anti-DEN virus response, we tested mice deficient in their IFN functions as potential models. Intraperitoneally administered mouse-adapted DEN 2 virus was uniformly lethal in AG129 mice (which lack alpha/beta IFN and gamma IFN receptor genes), regardless of age. Immunized mice were protected from virus challenge, and survival times increased following passive transfer of anti-DEN polyclonal antibody. These results demonstrate that AG129 mice are a promising small animal model for DEN virus vaccine trials. PMID:9847388

  5. Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

    PubMed Central

    Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

    2016-01-01

    Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

  6. Mouse Model of Human Breast Cancer Initiated by a Fusion Oncogene

    DTIC Science & Technology

    2006-09-01

    AD_________________ Award Number: W81XWH-05-1-0502 TITLE: Mouse Model of Human Breast Cancer ...TYPE Final 3. DATES COVERED (From - To) 15 AUG 2005 - 14 AUG 2006 4. TITLE AND SUBTITLE Mouse Model of Human Breast Cancer Initiated by a Fusion...SUPPLEMENTARY NOTES 14. ABSTRACT: In this study, we generated a novel mouse model of human breast cancer based on a recurrent chromosomal

  7. Altered Gastrointestinal Function in the Neuroligin-3 Mouse Model of Autism

    DTIC Science & Technology

    2013-10-01

    and aggression in a mouse model of autism . Invited manuscript: Swaminathan, M, Balasuriya, G, Hill-Yardin EL., Bornstein, JC. Video imaging of...the Neuroligin-3 Mouse Model of Autism PRINCIPAL INVESTIGATOR: Professor Joel Bornstein CONTRACTING ORGANIZATION: The University of...Gastrointestinal function in the Neuroligin-3 Mouse Model of Autism 5b. GRANT NUMBER W81XWH-12-1-0494 GRANT110132 47 GRANT110132 47 5c

  8. Cerebellar associative sensory learning defects in five mouse autism models

    PubMed Central

    Kloth, Alexander D; Badura, Aleksandra; Li, Amy; Cherskov, Adriana; Connolly, Sara G; Giovannucci, Andrea; Bangash, M Ali; Grasselli, Giorgio; Peñagarikano, Olga; Piochon, Claire; Tsai, Peter T; Geschwind, Daniel H; Hansel, Christian; Sahin, Mustafa; Takumi, Toru; Worley, Paul F; Wang, Samuel S-H

    2015-01-01

    Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2−/−, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models. DOI: http://dx.doi.org/10.7554/eLife.06085.001 PMID:26158416

  9. GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration

    PubMed Central

    Gómez-Sintes, Raquel; Hernández, Félix; Lucas, José J.; Avila, Jesús

    2011-01-01

    Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases. PMID:22110426

  10. A mouse model for Chlamydia suis genital infection.

    PubMed

    Donati, Manuela; Di Paolo, Maria; Favaroni, Alison; Aldini, Rita; Di Francesco, Antonietta; Ostanello, Fabio; Biondi, Roberta; Cremonini, Eleonora; Ginocchietti, Laura; Cevenini, Roberto

    2015-02-01

    A mouse model for Chlamydia suis genital infection was developed. Ninety-nine mice were randomly divided into three groups and intravaginally inoculated with chlamydia: 45 mice (group 1) received C. suis purified elementary bodies (EBs), 27 (group 2) were inoculated with C. trachomatis genotype E EBs and 27 mice (group 3) with C. trachomatis genotype F EBs. Additionally, 10 mice were used as a negative control. At seven days post-infection (dpi) secretory anti-C. suis IgA were recovered from vaginal swabs of all C. suis inoculated mice. Chlamydia suis was isolated from 93, 84, 71 and 33% vaginal swabs at 3, 5, 7 and 12 dpi. Chlamydia trachomatis genotype E and F were isolated from 100% vaginal swabs up to 7 dpi and from 61 and 72%, respectively, at 12 dpi. Viable C. suis and C. trachomatis organisms were isolated from uterus and tubes up to 16 and 28 dpi, respectively. The results of the present study show the susceptibility of mice to intravaginal inoculation with C. suis. A more rapid course and resolution of C. suis infection, in comparison to C. trachomatis, was highlighted. The mouse model could be useful for comparative investigations involving C. suis and C. trachomatis species.

  11. Omics analysis of mouse brain models of human diseases.

    PubMed

    Paban, Véronique; Loriod, Béatrice; Villard, Claude; Buee, Luc; Blum, David; Pietropaolo, Susanna; Cho, Yoon H; Gory-Faure, Sylvie; Mansour, Elodie; Gharbi, Ali; Alescio-Lautier, Béatrice

    2017-02-05

    The identification of common gene/protein profiles related to brain alterations, if they exist, may indicate the convergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse lines modelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, including transcriptomic and proteomic methods, were used. The gene/protein lists were used for inter-disease comparisons and further functional and network investigations. When the inter-disease comparison was performed using the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreased rapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was shared among 4 disorders, providing strong evidence that a common molecular signature does not exist among brain diseases. The inter-disease comparison of functional processes showed the involvement of a few major biological processes indicating that brain diseases of diverse aetiologies might utilize common biological pathways in the nervous system, without necessarily involving similar molecules.

  12. Paraquat toxicity in a mouse embryonic stem cell model.

    PubMed

    Perla, Venu; Perrin, Nancy A; Greenlee, Anne R

    2008-03-01

    The objective of this in vitro study was to use a mouse embryonic stem (mES) cell model to better understand pesticide injury that may adversely affect early pregnancy and to evaluate an antioxidant intervention. Undifferentiated D3 mES cells were incubated 24h with control, reference dose (RfD), no observed effect level (NOEL), or lowest observed effect level (LOEL) of paraquat, a commonly used, toxic agricultural herbicide. Pesticide effects were evaluated at 0 and 24h using assays for cell proliferation, total reactive oxygen species (ROS), viability, and alkaline phosphatase activity. Compared to 0 h, cell proliferation increased significantly in the 24h control treatment and was stalled in all paraquat dilutions tested. ROS production and percent necrotic and apoptotic cells were significantly increased at all paraquat concentrations examined. Alkaline phosphatase activity suggested that cells remained undifferentiated during the study period. Experiments with ascorbic acid suggested that pesticide effects on cell viability and ROS production were minimized by the recommended daily allowance (RDA) of vitamin C. Data suggest pesticide-induced injury can occur very early in development and at concentrations predicted without health consequences. Mouse ES cells may provide a useful in vitro model for rapidly screening developmental toxicants and protective interventions.

  13. L1 integration in a transgenic mouse model

    PubMed Central

    Babushok, Daria V.; Ostertag, Eric M.; Courtney, Christine E.; Choi, Janice M.; Kazazian, Haig H.

    2006-01-01

    To study integration of the human LINE-1 retrotransposon (L1) in vivo, we developed a transgenic mouse model of L1 retrotransposition that displays de novo somatic L1 insertions at a high frequency, occasionally several insertions per mouse. We mapped 3′ integration sites of 51 insertions by Thermal Asymmetric Interlaced PCR (TAIL–PCR). Analysis of integration locations revealed a broad genomic distribution with a modest preference for intergenic regions. We characterized the complete structures of 33 de novo retrotransposition events. Our results highlight the large number of highly truncated L1s, as over 52% (27/51) of total integrants were <1/3 the length of a full-length element. New integrants carry all structural characteristics typical of genomic L1s, including a number with inversions, deletions, and 5′-end microhomologies to the target DNA sequence. Notably, at least 13% (7/51) of all insertions contain a short stretch of extra nucleotides at their 5′ end, which we postulate result from template-jumping by the L1-encoded reverse transcriptase. We propose a unified model of L1 integration that explains all of the characteristic features of L1 retrotransposition, such as 5′ truncations, inversions, extra nucleotide additions, and 5′ boundary and inversion point microhomologies. PMID:16365384

  14. Modeling of optical quadrature microscopy for imaging mouse embryos

    NASA Astrophysics Data System (ADS)

    Warger, William C., II; DiMarzio, Charles A.

    2008-02-01

    Optical quadrature microscopy (OQM) has been shown to provide the optical path difference through a mouse embryo, and has led to a novel method to count the total number of cells further into development than current non-toxic imaging techniques used in the clinic. The cell counting method has the potential to provide an additional quantitative viability marker for blastocyst transfer during in vitro fertilization. OQM uses a 633 nm laser within a modified Mach-Zehnder interferometer configuration to measure the amplitude and phase of the signal beam that travels through the embryo. Four cameras preceded by multiple beamsplitters record the four interferograms that are used within a reconstruction algorithm to produce an image of the complex electric field amplitude. Here we present a model for the electric field through the primary optical components in the imaging configuration and the reconstruction algorithm to calculate the signal to noise ratio when imaging mouse embryos. The model includes magnitude and phase errors in the individual reference and sample paths, fixed pattern noise, and noise within the laser and detectors. This analysis provides the foundation for determining the imaging limitations of OQM and the basis to optimize the cell counting method in order to introduce additional quantitative viability markers.

  15. A polygenic burden of rare disruptive mutations in schizophrenia

    PubMed Central

    Purcell, Shaun M.; Moran, Jennifer L.; Fromer, Menachem; Ruderfer, Douglas; Solovieff, Nadia; Roussos, Panos; O’Dushlaine, Colm; Chambert, Kimberly; Bergen, Sarah E.; Kähler, Anna; Duncan, Laramie; Stahl, Eli; Genovese, Giulio; Fernández, Esperanza; Collins, Mark O; Komiyama, Noboru H.; Choudhary, Jyoti S.; Magnusson, Patrik K. E.; Banks, Eric; Shakir, Khalid; Garimella, Kiran; Fennell, Tim; de Pristo, Mark; Grant, Seth G.N.; Haggarty, Stephen; Gabriel, Stacey; Scolnick, Edward M.; Lander, Eric S.; Hultman, Christina; Sullivan, Patrick F.; McCarroll, Steven A.; Sklar, Pamela

    2014-01-01

    By analyzing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we have demonstrated a polygenic burden primarily arising from rare (<1/10,000), disruptive mutations distributed across many genes. Especially enriched genesets included the voltage-gated calcium ion channel and the signaling complex formed by the activity-regulated cytoskeleton-associated (ARC) scaffold protein of the postsynaptic density (PSD), sets previously implicated by genome-wide association studies (GWAS) and copy-number variation (CNV) studies. Similar to reports in autism, targets of the fragile × mental retardation protein (FMRP, product of FMR1) were enriched for case mutations. No individual gene-based test achieved significance after correction for multiple testing and we did not detect any alleles of moderately low frequency (~0.5-1%) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene mapping paradigms in neuropsychiatric disease. PMID:24463508

  16. Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

    PubMed Central

    Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K; Johnson, Jessica S; Kavanagh, David H; Perumal, Thanneer M; Ruderfer, Douglas M; Oh, Edwin C; Topol, Aaron; Shah, Hardik R; Klei, Lambertus L; Kramer, Robin; Pinto, Dalila; Gümüş, Zeynep H; Cicek, A. Ercument; Dang, Kristen K; Browne, Andrew; Lu, Cong; Xie, Lu; Readhead, Ben; Stahl, Eli A; Parvizi, Mahsa; Hamamsy, Tymor; Fullard, John F; Wang, Ying-Chih; Mahajan, Milind C; Derry, Jonathan M J; Dudley, Joel; Hemby, Scott E; Logsdon, Benjamin A; Talbot, Konrad; Raj, Towfique; Bennett, David A; De Jager, Philip L; Zhu, Jun; Zhang, Bin; Sullivan, Patrick F; Chess, Andrew; Purcell, Shaun M; Shinobu, Leslie A; Mangravite, Lara M; Toyoshiba, Hiroyoshi; Gur, Raquel E; Hahn, Chang-Gyu; Lewis, David A; Haroutunian, Vahram; Peters, Mette A; Lipska, Barbara K; Buxbaum, Joseph D; Schadt, Eric E; Hirai, Keisuke; Roeder, Kathryn; Brennand, Kristen J; Katsanis, Nicholas; Domenici, Enrico; Devlin, Bernie; Sklar, Pamela

    2016-01-01

    Over 100 genetic loci harbor schizophrenia associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of schizophrenia cases (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ~20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3, or SNAP91. Altering expression of FURIN, TSNARE1, or CNTN4 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases. PMID:27668389

  17. Chronic mouse model of TMA-induced contact hypersensitivity.

    PubMed

    Schneider, Claudia; Döcke, Wolf-Dietrich F; Zollner, Thomas M; Röse, Lars

    2009-04-01

    Due to the steadily increasing incidence of atopic dermatitis (AD), especially in children, there is a high medical need for new therapies and improved animal models. In mice, trimellitic anhydride (TMA) is routinely used to trigger T-cell-dependent contact hypersensitivity (CHS) reactions. In this study, we compared the standard acute TMA-induced CHS in Balb/c mice with subacute and chronic models of TMA-induced ear inflammation. Compared to the acute model, the chronic CHS model more closely reflects characteristics of AD, such as typical morphological changes of the inflamed skin, strong infiltration with T cells, major histocompatibility complex II-positive cells, eosinophils, and mast cells, a T-helper cell-type (Th) 2 cytokine profile and a strong increase of serum IgE levels. Moreover, a strong lymph node involvement with T-helper cell dominance and a mixed Th1/Th2 T-cell differentiation and activation pattern was demonstrated. Importantly, as demonstrated by successful therapy with prednisolone, the chronic TMA-induced CHS model, in contrast to acute and subacute models, made prolonged therapeutic treatment of a pre-established skin inflammation possible. Altogether, we present an improved model of mouse T-cell-dependent skin inflammation for AD. We hope this model will enhance the predictive value of animal models for therapeutic treatment of atopic eczema.

  18. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness.

    PubMed

    Bigdeli, Tim B; Ripke, Stephan; Bacanu, Silviu-Alin; Lee, Sang Hong; Wray, Naomi R; Gejman, Pablo V; Rietschel, Marcella; Cichon, Sven; St Clair, David; Corvin, Aiden; Kirov, George; McQuillin, Andrew; Gurling, Hugh; Rujescu, Dan; Andreassen, Ole A; Werge, Thomas; Blackwood, Douglas H R; Pato, Carlos N; Pato, Michele T; Malhotra, Anil K; O'Donovan, Michael C; Kendler, Kenneth S; Fanous, Ayman H

    2016-03-01

    Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant

  19. Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study

    PubMed Central

    Trotta, Antonella; Iyegbe, Conrad; Di Forti, Marta; Sham, Pak C.; Campbell, Desmond D.; Cherny, Stacey S.; Mondelli, Valeria; Aitchison, Katherine J.; Murray, Robin M.

    2016-01-01

    A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis. PMID:27648571

  20. Evidence of Polygenic Adaptation in the Systems Genetics of Anthropometric Traits

    PubMed Central

    Polimanti, Renato; Yang, Bao Zhu; Zhao, Hongyu; Gelernter, Joel

    2016-01-01

    Many signals of natural selection have been identified in the human genome. However, except for some single-locus mechanisms, most molecular processes generating these adaptation signals are still unknown. We developed an approach that integrates datasets related to genome-wide association studies (GWAS) with information about systems biology and genetic signatures of natural selection to identify evidence of polygenic adaptation. Specifically, we focused on five anthropometric measurements: body mass index (BMI), height, waist-to-hip ratio adjusted for BMI (WHR), and waist circumference adjusted for BMI (WC), and sex differences for WHR and WC. We performed an enrichment analysis for signals of natural selection in protein interaction networks associated with anthropometric traits in European populations. The adaptation signals-enriched gene networks associated highlighted epistatic interactions in the context of polygenic selection for the investigated traits. These polygenic mechanisms indicated intriguing selective mechanisms related to the anthropometric traits: adult locomotory behavior for BMI, infection resistance for height, interplay between lipid transport and immune systems for WHR, and female-specific polygenic adaptation for WHR and WC. In conclusion, we observed evidence of polygenic adaptation in the context of systems genetics of anthropometric traits that indicates polygenic mechanisms related to the natural selection in European populations. PMID:27537407

  1. Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample

    PubMed Central

    Papiol, S; Mitjans, M; Assogna, F; Piras, F; Hammer, C; Caltagirone, C; Arias, B; Ehrenreich, H; Spalletta, G

    2014-01-01

    A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores—using single nucleotide polymorphism (SNP) information of SCZ GWAS—(polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample. PMID:24548877

  2. Insights into granulosa cell tumors using spontaneous or genetically engineered mouse models

    PubMed Central

    2016-01-01

    Granulosa cell tumors (GCTs) are rare sex cord-stromal tumors that have been studied for decades. However, their infrequency has delayed efforts to research their etiology. Recently, mutations in human GCTs have been discovered, which has led to further research aimed at determining the molecular mechanisms underlying the disease. Mouse models have been important tools for studying GCTs, and have provided means to develop and improve diagnostics and therapeutics. Thus far, several genetically modified mouse models, along with one spontaneous mouse model, have been reported. This review summarizes the phenotypes of these mouse models and their applicability in elucidating the mechanisms of granulosa cell tumor development. PMID:27104151

  3. Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

    PubMed

    Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

    2015-02-01

    During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

  4. Gait analysis in a mouse model resembling Leigh disease.

    PubMed

    de Haas, Ria; Russel, Frans G; Smeitink, Jan A

    2016-01-01

    Leigh disease (LD) is one of the clinical phenotypes of mitochondrial OXPHOS disorders and also known as sub-acute necrotizing encephalomyelopathy. The disease has an incidence of 1 in 77,000 live births. Symptoms typically begin early in life and prognosis for LD patients is poor. Currently, no clinically effective treatments are available. Suitable animal and cellular models are necessary for the understanding of the neuropathology and the development of successful new therapeutic strategies. In this study we used the Ndufs4 knockout (Ndufs4(-/-)) mouse, a model of mitochondrial complex I deficiency. Ndusf4(-/-) mice exhibit progressive neurodegeneration, which closely resemble the human LD phenotype. When dissecting behavioral abnormalities in animal models it is of great importance to apply translational tools that are clinically relevant. To distinguish gait abnormalities in patients, simple walking tests can be assessed, but in animals this is not easy. This study is the first to demonstrate automated CatWalk gait analysis in the Ndufs4(-/-) mouse model. Marked differences were noted between Ndufs4(-/-) and control mice in dynamic, static, coordination and support parameters. Variation of walking speed was significantly increased in Ndufs4(-/-) mice, suggesting hampered and uncoordinated gait. Furthermore, decreased regularity index, increased base of support and changes in support were noted in the Ndufs4(-/-) mice. Here, we report the ability of the CatWalk system to sensitively assess gait abnormalities in Ndufs4(-/-) mice. This objective gait analysis can be of great value for intervention and drug efficacy studies in animal models for mitochondrial disease.

  5. Dysregulation of bile acid homeostasis in parenteral nutrition mouse model

    PubMed Central

    Zhan, Le; Yang, Ill; Shen, Jianliang; Gorczyca, Ludwik; Memon, Naureen; Buckley, Brian T.

    2015-01-01

    Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12α-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-α (LXRα) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-α (RORα) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXRα function. Western blot showed significantly reduced nuclear migration of RORα protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver RORα signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD. PMID:26564717

  6. Endpoints for Mouse Abdominal Tumor Models: Refinement of Current Criteria

    PubMed Central

    Paster, Eden V; Villines, Kimberly A; Hickman, Debra L

    2009-01-01

    Accurate, rapid, and noninvasive health assessments are required to establish more appropriate endpoints in mouse cancer models where tumor size is not easily measured. We evaluated potential endpoints in mice with experimentally induced peritoneal lymphoma, an abdominal tumor model, by comparing body weight, body condition, and behavior with those of a control group of mice not developing lymphoma. Our hypothesis was that body weight would increase or plateau, whereas body condition and behavioral scores would decrease, as disease progressed. Results indicated that body weight did not differ significantly between the control and experimental groups, but the experimental group experienced significant decreases in both body condition and behavioral scores. Our results support the use of body condition and behavioral scoring as adjunctive assessment methods for mice involved in abdominal lymphoma tumor studies in which health may decline despite an increase or plateau in body weight. PMID:19619413

  7. Skin Carcinogenesis Studies Using Mouse Models with Altered Polyamines

    PubMed Central

    Nowotarski, Shannon L; Feith, David J; Shantz, Lisa M

    2015-01-01

    Nonmelanoma skin cancer (NMSC) is a major health concern worldwide. With increasing numbers in high-risk groups such as organ transplant recipients and patients taking photosensitizing medications, the incidence of NMSC continues to rise. Mouse models of NMSC allow us to better understand the molecular signaling cascades involved in skin tumor development in order to identify novel therapeutic strategies. Here we review the models designed to determine the role of the polyamines in NMSC development and maintenance. Elevated polyamines are absolutely required for tumor growth, and dysregulation of their biosynthetic and catabolic enzymes has been observed in NMSC. Studies using mice with genetic alterations in epidermal polyamines suggest that they play key roles in tumor promotion and epithelial cell survival pathways, and recent clinical trials indicate that pharmacological inhibitors of polyamine metabolism show promise in individuals at high risk for NMSC. PMID:26380554

  8. Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia.

    PubMed

    McMackin, Marissa Z; Henderson, Chelsea K; Cortopassi, Gino A

    2017-01-01

    Friedreich's Ataxia (FA) is a pediatric neurodegenerative disease whose clinical presentation includes ataxia, muscle weakness, and peripheral sensory neuropathy. The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA, which currently has no approved therapy. We tested 13 neurobehavioral tasks to identify a robust KIKO phenotype: Open Field, Grip Strength Test(s), Cylinder, Skilled Forelimb Grasp Task(s), Treadmill Endurance, Locotronic Motor Coordination, Inverted Screen, Treadscan, and Von Frey. Of these, Inverted Screen, Treadscan and Von Frey produced significant neurobehavioral deficits at >8 months of age, and relate to the clinically relevant endpoints of muscle strength and endurance, gait ataxia, and peripheral insensitivity. Thus we identify robust phenotypic measures related to Friedreich's ataxia clinical endpoints which could be used to test effectiveness of potential drug therapy.

  9. Neural Mechanisms Contributing to Dysphagia in Mouse Models.

    PubMed

    Hinkel, Cameron J; Sharma, Rishi; Thakkar, Mahesh M; Takahashi, Kazutaka; Hopewell, Bridget L; Lever, Teresa E

    2016-08-01

    Investigative research into curative treatments for dysphagia is hindered by our incomplete understanding of the neural mechanisms of swallowing in health and disease. Development of translational research models is essential to bridge this knowledge gap by fostering innovative methodology. Toward this goal, our laboratory has developed a translational research assessment tool to investigate the neural mechanistic control of swallowing in unrestrained, self-feeding mice. Here we describe our initial development of synchronous brainstem neural recordings with a videofluoroscopic swallow study assay in healthy mice across the life span. Refinement of this combined methodology is currently underway. Ultimately, we envision that this assessment tool will permit systematic analysis of therapeutic interventions for dysphagia in preclinical trials with numerous mouse models of human conditions that cause dysphagia, such as amyotrophic lateral sclerosis, Parkinson's disease, stroke, and advanced aging.

  10. IGF-1 and Bone: New Discoveries From Mouse Models

    PubMed Central

    Yakar, Shoshana; Courtland, Hayden-William; Clemmons, David

    2010-01-01

    Insulin-like growth factor-1 (IGF-1) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early during development and its effects are mediated through binding to a tyrosine kinase receptor, the insulin-like growth factor-1 receptor (IGF-1R). In the circulation, the IGFs bind to IGF-binding proteins (IGFBPs), which determine their bioavailability and regulate the interaction between the IGFs and IGF-1R. Studies in animal models and in humans have established critical roles for IGFs in skeletal growth and development. In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology. © 2010 American Society for Bone and Mineral Research. PMID:20836088

  11. Establishment of a Novel Mouse Model of Coronary Microembolization

    PubMed Central

    Cao, Yuan-Yuan; Chen, Zhang-Wei; Jia, Jian-Guo; Chen, Ao; Zhou, You; Ye, Yong; Gao, Yan-Hua; Xia, Yan; Chang, Shu-Fu; Ma, Jian-Ying; Qian, Ju-Ying; Ge, Jun-Bo

    2016-01-01

    Background: Coronary microembolization (CME) has been frequently seen in acute coronary syndromes and percutaneous coronary intervention. Small animal models are required for further studies of CME related to severe prognosis. This study aimed to explore a new mouse model of CME. Methods: The mouse model of CME was established by injecting polystyrene microspheres into the left ventricular chamber during 15-s occlusion of the ascending aorta. Based on the average diameter and dosage used, 30 C57BL/6 male mice were randomly divided into five groups (n = 6 in each): 9 μm/500,000, 9 μm/800,000, 17 μm/200,000, 17 μm/500,000, and sham groups. The postoperative survival and performance of the mice were recorded. The mice were sacrificed 3 or 10 days after the surgery. The heart tissues were harvested for hematoxylin and eosin staining and Masson trichrome staining to compare the extent of inflammatory cellular infiltration and fibrin deposition among groups and for scanning transmission electron microscopic examinations to see the ultrastructural changes after CME. Results: Survival analysis demonstrated that the cumulative survival rate of the 17 μm/500,000 group was significantly lower than that of the sham group (0/6 vs. 6/6, P = 0.001). The cumulative survival rate of the 17 μm/200,000 group was lower than those of the sham and 9 μm groups with no statistical difference (cumulative survival rate of the 17 μm/200,000, 9 μm/800,000, 9 μm/500,000, and sham groups was 4/6, 5/6, 6/6, and 6/6, respectively). The pathological alterations were similar between the 9 μm/500,000 and 9 μm/800,000 groups. The extent of inflammatory cellular infiltration and fibrin deposition was more severe in the 17 μm/200,000 group than in the 9 μm/500,000 and 9 μm/800,000 groups 3 and 10 days after the surgery. Scanning transmission electron microscopic examinations revealed platelet aggregation and adhesion, microthrombi formation, and changes in cardiomyocytes. Conclusion: The

  12. A mouse model for juvenile doxorubicin-induced cardiac dysfunction.

    PubMed

    Zhu, Wuqiang; Shou, Weinian; Payne, R Mark; Caldwell, Randall; Field, Loren J

    2008-11-01

    Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.

  13. Placental Development in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Van Granigen Caesar, Gerialisa; Dale, Jeffrey M.; Osman, Erkan Y.; Garcia, Michael L.; Lorson, Christian L.; Schulz, Laura C.

    2016-01-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder, leading to fatal loss of motor neurons. It is caused by loss of function of the SMN gene, which is expressed throughout the body, and there is increasing evidence of dysfunction in non-neuronal tissues. Birthweight is one of most powerful prognostic factors for infants born with SMA, and intrauterine growth restriction is common. In the SMNΔ7 mouse model of SMA, pups with the disease lived 25% longer when their mothers were fed a higher fat, “breeder” diet. The placenta is responsible for transport of nutrients from mother to fetus, and is a major determinant of fetal growth. Thus, the present study tested the hypothesis that placental development is impaired in SMNΔ7 conceptuses. Detailed morphological characterization revealed no defects in SMNΔ7 placental development, and expression of key transcription factors regulating mouse placental development was unaffected. The intrauterine growth restriction observed in SMA infants likely does not result from impaired placental development. PMID:26748185

  14. Disease model curation improvements at Mouse Genome Informatics

    PubMed Central

    Bello, Susan M.; Richardson, Joel E.; Davis, Allan P.; Wiegers, Thomas C.; Mattingly, Carolyn J.; Dolan, Mary E.; Smith, Cynthia L.; Blake, Judith A.; Eppig, Janan T.

    2012-01-01

    Optimal curation of human diseases requires an ontology or structured vocabulary that contains terms familiar to end users, is robust enough to support multiple levels of annotation granularity, is limited to disease terms and is stable enough to avoid extensive reannotation following updates. At Mouse Genome Informatics (MGI), we currently use disease terms from Online Mendelian Inheritance in Man (OMIM) to curate mouse models of human disease. While OMIM provides highly detailed disease records that are familiar to many in the medical community, it lacks structure to support multilevel annotation. To improve disease annotation at MGI, we evaluated the merged Medical Subject Headings (MeSH) and OMIM disease vocabulary created by the Comparative Toxicogenomics Database (CTD) project. Overlaying MeSH onto OMIM provides hierarchical access to broad disease terms, a feature missing from the OMIM. We created an extended version of the vocabulary to meet the genetic disease-specific curation needs at MGI. Here we describe our evaluation of the CTD application, the extensions made by MGI and discuss the strengths and weaknesses of this approach. Database URL: http://www.informatics.jax.org/ PMID:22434831

  15. EGFR-specific nanoprobe biodistribution in mouse models

    NASA Astrophysics Data System (ADS)

    Fashir, Samia A.; Castilho, Maiara L.; Hupman, Michael A.; Lee, Christopher L. D.; Raniero, Leandro J.; Alwayn, Ian; Hewitt, Kevin C.

    2015-06-01

    Nanotechnology offers a targeted approach to both imaging and treatment of cancer, the leading cause of death worldwide. Previous studies have found nanoparticles with a wide variety of coatings initiate an immune response leading to sequestration in the liver and spleen. In an effort to find a nanoparticle platform which does not elicit an immune response we created 43/44 nm gold or silver nanoparticles coated with biomolecules normally produced by the body, α-lipoic acid and the Epidermal Growth Factor (EGF), and have used mass spectroscopy to determine their biodistribution in mouse models, 24 hours following tail vein injection. Relative to controls, mouse EGF (mEGF) coated silver and gold nanoprobes are found at reduced levels in the liver and spleen. mEGF coated gold nanoprobes on the other hand do not appear to elicit any immune response, as they are found at background levels in these organs. As a result they should remain in circulation for longer and accumulate at high levels in tumors by the enhanced permeability retention (EPR) effect.

  16. Growth plate abnormalities in a new dwarf mouse model: tich.

    PubMed

    Brown, R A; Bird, L; Blunn, G W; Archer, J R

    1994-03-01

    Growth plate cartilage calcification has been examined in a recently described mouse mutant, tich, which is co-isogenic with the A.TL strain. Long bones were studied from 1-day-old and 1-month-old mice which carried a homozygous recessive gene mutation making them short limbed and dumpy. Specimens were studied by routine histology, scanning electron microscopy and radiography. In 1-day-old tich mice the front of calcified cartilage was recessed behind the advancing periosteum and bone. No similar recess was seen in control mice. At 1 month of age, a number of the long bone growth plates were irregularly thickened, particularly in the central area. This produced a central tongue of non-calcified cartilage (particularly prominent in the proximal tibia) which gave rise to a corresponding pit in the calcified cartilage layer, in macerated specimens. This was accompanied by poor resorption of calcified cartilage. At both ages the presence of the respective defects was radiographically confirmed. At present it is not known whether this is primarily a defect of calcification or resorption but its presence, apparently from a single mutation in a genetically defined mouse strain, makes it a potentially valuable model.

  17. A Mouse Model for Human Unstable Hemoglobin Santa Ana.

    PubMed

    Miyashiro, Samantha I; Massironi, Silvia M G; Mori, Claudia M C; Cruz, Carolina C; Hagiwara, Mitika K; Maiorka, Paulo C

    2016-12-01

    In the present study, we described the phenotype, histologic morphology, and molecular etiology of a mouse model of unstable hemoglobin Santa Ana. Hematologic evaluation of anemic mice (Anem/+) discovered after N-ethyl-N-nitrosourea mutagenesis revealed moderate anemia with intense reticulocytosis and polychromasia, followed by anisocytosis, macrocytosis, hypochromia, and intraerythrocytic inclusion and Heinz bodies. The mice also demonstrated hemoglobinuria, bilirubinemia, and erythrocytic populations with differing resistance to osmotic lysis. Splenomegaly (particularly in older mutant mice) and jaundice were apparent at necropsy. Histopathologic examination revealed dramatically increased hematopoiesis and hemosiderosis in hematopoietic organs and intracellular iron deposition in tubular renal cells. These data are characteristic of a congenital hemolytic regenerative anemia, similar to human anemias due to unstable hemoglobin. Genetic mapping assigned the affected gene to mouse chromosome 7, approximately 50 cM from the Hbb locus. The sequence of the mutant Hbb gene exhibited a T→C transversion at nucleotide 179 in Hbb-b1, leading to the substitution of proline for leucine at amino acid residue 88 and thus homologous to the genetic defect underlying Santa Ana anemia in humans.

  18. The first knockin mouse model of episodic ataxia type 2.

    PubMed

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes.

  19. Pathogenicity of Conidiobolus coronatus and Fusarium solani in mouse models.

    PubMed

    Li, Yadi; Fang, Xiangang; Zhou, Xiaoqian; Geng, Suying; Wang, Yuxin; Yang, Xiumin

    2017-02-27

    To study the pathogenicity of Conidiobolus coronatus (C. coronatus) and Fusarium solani (F. solani) in animal models. Immunocompromised mice were treated with cyclophosphamide and prednisolone via intraperitoneal injection before and after inoculation. According to pathogenic characteristics of different fungi, C. coronatus was used to infect mice via intravenous inoculation, intraperitoneal inoculation, gastrointestinal infusion and intradermal inoculation methods. And F. solani was used to infect mice by inoculation via the abraded or normal skin. In the group of immunocompromised mice, C. coronatus was isolated from the lung tissues of one mouse on day 7 and another on day 10 respectively. The corresponding histopathology revealed infiltration of local inflammatory cells in the lung tissue. Pathogenic lesions were observed in all normal and immunocompromised mice infected with F. solani via abraded skin. The lesions in the immunocompromised mice were more severe and persisted longer than those in the normal mice. Moreover, hyphae were mostly observed in the histopathological examination and fungal culture from the immunocompromised mouse. The pathogenicity of C. coronatus was relatively weak as it did not induce local infections and did not disseminate the disease in immunocompetent and immunocompromised mice. Therefore, F. solani is a type of opportunistic pathogenic fungus, and abraded skin is one of the causative routes of infection.

  20. Preclinical humanized mouse model with ectopic ovarian tissues

    PubMed Central

    FU, SHILONG; WANG, JUE; SUN, WU; XU, YI; ZHOU, XIAOYU; CHENG, WENJUN

    2014-01-01

    The aim of the present study was to establish human ovarian stroma within the mouse subcutaneously, in order for the resulting stroma to serve as a useful preclinical tool to study the progression of human ovarian cancer in a humanized ovarian microenvironment. Normal human ovarian tissues were subcutaneously implanted into severe combined immunodeficient (SCID) mice and then the implants were identified by immunohistochemistry. The implants became vascularized and retained their original morphology for about 4 weeks following implantation. Immunohistochemical staining for cytokeratin-7 confirmed the ovarian origin of the epithelial cells. CD34 staining demonstrated human-derived vessels. Positive estrogen receptor and partially-positive progesterone receptor staining indicated the estrogen and progesterone dependence of the implants. Only vascular pericytes expressed α-smooth muscle actin, indicating the normal ovarian origin of the xenografts. Human ovarian tissue successfully survived in SCID mice and retained its original properties. This humanized mouse model may be used as preclinical tool to investigate ovarian cancer. PMID:25120592

  1. Beethoven, a mouse model for dominant, progressive hearing loss DFNA36.

    PubMed

    Vreugde, Sarah; Erven, Alexandra; Kros, Corné J; Marcotti, Walter; Fuchs, Helmut; Kurima, Kiyoto; Wilcox, Edward R; Friedman, Thomas B; Griffith, Andrew J; Balling, Rudi; Hrabé De Angelis, Martin; Avraham, Karen B; Steel, Karen P

    2002-03-01

    Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn) are mouse models, respectively.

  2. The nude mouse model for the study of human skin disorders.

    PubMed

    Gilhar, A; Etzioni, A

    1994-01-01

    Normal human skin grafted onto the nude mouse can be maintained without any signs of rejection throughout the life-span of the animal. Indeed, the nude mouse model is a powerful tool for understanding the pathological process of the skin. Until now many skin diseases such as psoriasis, cutaneous lupus, pemphigus and vitiligo have been looked at using the nude mouse model, which has helped to clarify the role of the various factors involved.

  3. Development of a syngeneic mouse model of epithelial ovarian cancer

    PubMed Central

    2010-01-01

    Background Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies. Methods Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no susceptibility to tumor development. Independent murine ovarian carcinoma (MOVCAR) cell lines were established from the ascites of tumor-bearing C57BL/6 TgMISIIR-TAg transgenic mice, characterized and tested for engraftment in the following recipient mice: 1) severe immunocompromised immunodeficient (SCID), 2) wild type C57BL/6, 3) oophorectomized tumor-prone C57BL/6 TgMISIIR-TAg transgenic and 4) non-tumor prone C57BL/6 TgMISIIR-TAg-Low transgenic. Lastly, MOVCAR cells transduced with a luciferase reporter were implanted in TgMISIIR-TAg-Low mice and in vivo tumor growth monitored by non-invasive optical imaging. Results Engraftment of MOVCAR cells by i.p. injection resulted in the development of disseminated peritoneal carcinomatosis in SCID, but not wild type C57BL/6 mice. Oophorectomized tumor-prone TgMISIIR-TAg mice developed peritoneal carcinomas with high frequency, rendering them unsuitable as allograft recipients. Orthotopic or pseudo-orthotopic implantation of MOVCAR cells in TgMISIIR-TAg-Low mice resulted in the development of disseminated peritoneal tumors, frequently accompanied by the production of malignant ascites. Tumors arising in the engrafted mice bore histopathological resemblance to human high-grade serous EOC and exhibited a similar pattern of peritoneal

  4. Transgenic Mouse Models of Childhood Onset Psychiatric Disorders

    PubMed Central

    Robertson, Holly R.; Feng, Guoping

    2011-01-01

    Childhood onset psychiatric disorders, such as Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Mood Disorders, Obsessive Compulsive Spectrum Disorders (OCSD), and Schizophrenia (SZ), affect many school age children leading to a lower quality of life, including difficulties in school and personal relationships that persists into adulthood. Currently, the causes of these psychiatric disorders are poorly understood resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, Mood Disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Animal models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single animal model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing transgenic mouse models for childhood onset psychiatric disorders. We compare the strength and weakness of various transgenic animal models proposed for each of the common childhood onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools. PMID:21309772

  5. A Neonatal Mouse Spinal Cord Compression Injury Model

    PubMed Central

    Züchner, Mark; Glover, Joel C.; Boulland, Jean-Luc

    2016-01-01

    Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life1, this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques1. Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections1. PMID:27078037

  6. Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

    PubMed Central

    Lidster, Katie; Jackson, Samuel J.; Ahmed, Zubair; Munro, Peter; Coffey, Pete; Giovannoni, Gavin; Baker, Mark D.; Baker, David

    2013-01-01

    Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment. PMID:24223903

  7. Genetically modified mouse models for oral drug absorption and disposition.

    PubMed

    Tang, Seng Chuan; Hendrikx, Jeroen J M A; Beijnen, Jos H; Schinkel, Alfred H

    2013-12-01

    Intestinal absorption is an essential step in the therapeutic use of most orally administered drugs and often mediated by enterocyte transmembrane transporters. Here we discuss several of these drug transport systems and knockout mouse models to study them. These studies showed that Multidrug resistance-associated protein 2 (Mrp2) can limit intestinal drug absorption. Organic cation transporter n1 (Octn1) and Octn2 might also facilitate intestinal drug absorption, although direct in vivo evidence is lacking. On the other hand, intestinal uptake of drugs is facilitated by the Equilibrative nucleoside transporter 1 (Ent1), Mrp3 and possibly Mrp4. No significant role in intestinal absorption for Oct1 and Oct2 or for Organic anion-transporting polypeptides (Oatp) 1a and 1b was found so far.

  8. Mechanisms of protective immunity in Hymenolepis nana/mouse model.

    PubMed

    Bortoletti, G; Gabriele, F; Palmas, C

    1992-12-01

    Some immunological and parasitological aspects related to the infection of Hymenolepsis nana in mice are summarized in this review, focusing on the immune effector mechanisms involved in this host/parasite relationship. H. nana is a small cestode tapeworm of man and mice. A primary egg-infection determines within few days a strong immunity. Immunity elicited by low-level primary infection is effective as a high-level infection. The protective role of both humoral and cell-mediated immunity is summarized. The histological findings demonstrate that eosinophils and mast-cells are implicated as effector cells. This review is an attempt to re-examine, at low-level infection, the immune mechanisms in H. nana/mouse model.

  9. Transgenic Mouse Models Enabling Photolabeling of Individual Neurons In Vivo

    PubMed Central

    Peter, Manuel; Bathellier, Brice; Fontinha, Bruno; Pliota, Pinelopi; Haubensak, Wulf; Rumpel, Simon

    2013-01-01

    One of the biggest tasks in neuroscience is to explain activity patterns of individual neurons during behavior by their cellular characteristics and their connectivity within the neuronal network. To greatly facilitate linking in vivo experiments with a more detailed molecular or physiological analysis in vitro, we have generated and characterized genetically modified mice expressing photoactivatable GFP (PA-GFP) that allow conditional photolabeling of individual neurons. Repeated photolabeling at the soma reveals basic morphological features due to diffusion of activated PA-GFP into the dendrites. Neurons photolabeled in vivo can be re-identified in acute brain slices and targeted for electrophysiological recordings. We demonstrate the advantages of PA-GFP expressing mice by the correlation of in vivo firing rates of individual neurons with their expression levels of the immediate early gene c-fos. Generally, the mouse models described in this study enable the combination of various analytical approaches to characterize living cells, also beyond the neurosciences. PMID:23626779

  10. Modeling diseases in multiple mouse strains for precision medicine studies.

    PubMed

    Klein, Andrés D

    2017-03-01

    The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for genome-wide association studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci, and their single nucleotide polymorphisms catalogs are known and freely available, facilitating the bioinformatics and reducing the costs of the study, since it is not required to genotype every mouse. This kind of approach can be applied to pharmacogenomics studies as well.

  11. Gene Therapy in Mouse Models of Huntington Disease

    PubMed Central

    Southwell, Amber L.; Patterson, Paul H.

    2011-01-01

    Huntingtin, the protein that when mutated causes Huntington disease (HD), has many known interactors and participates in diverse cellular functions. Mutant Htt (mHtt) engages in a variety of aberrant interactions that lead to pathological gain of toxic functions as well as loss of normal functions. The broad symptomatology of HD, including diminished voluntary motor control, cognitive decline, and psychiatric disturbances, reflects the multifaceted neuropathology. Although currently available therapies for HD focus on symptom management, the autosomal dominant cause and the adult onset make this disease an ideal candidate for genetic intervention. A variety of gene therapy approaches have been tested in mouse models of HD, ranging from those aimed at ameliorating downstream pathology or replacing lost neuronal populations to more upstream strategies to reduce mHtt levels. Here the authors review the results of these preclinical trials. PMID:21489966

  12. Lessons Learned from Mouse Mammary Tumor Virus in Animal Models

    PubMed Central

    Dudley, Jaquelin P.; Golovkina, Tatyana V.; Ross, Susan R.

    2016-01-01

    Mouse mammary tumor virus (MMTV), which was discovered as a milk-transmitted, infectious, cancer-inducing agent in the 1930s, has been used as an animal model for the study of retroviral infection and transmission, antiviral immune responses, and breast cancer and lymphoma biology. The main target cells for MMTV infection in vivo are cells of the immune system and mammary epithelial cells. Although the host mounts an immune response to the virus, MMTV has evolved multiple means of evading this response. MMTV causes mammary tumors when the provirus integrates into the mammary epithelial and lymphoid cell genome during viral replication and thereby activates cellular oncogene expression. Thus, tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer. PMID:27034391

  13. Mouse models for the evaluation of osteocyte functions.

    PubMed

    Komori, Toshihisa

    2014-02-01

    Osteocytes establish an extensive intracellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface. To examine the osteocyte function, several mouse models were established. To ablate osteocytes, osteocytes death was induced by diphtheria toxin. However, any types of osteocyte death result in necrosis, because dying osteocytes are not phagocytosed by scavengers. After the rupture of cytoplasmic membrane, immunostimulatory molecules are released from lacunae to bone surface through canaliculi, and stimulate macrophages. The stimulated macrophages produce interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which are the most important proinflammatory cytokines triggering inflammatory bone loss. Therefore, the osteocyte ablation results in necrosis-induced severe osteoporosis. In conditional knockout mice of gap junction protein alpha-1 (GJA1), which encodes connexin 43 in Gap junction, using dentin matrix protein 1 (DMP1) Cre transgenic mice, osteocyte apoptosis and enhanced bone resorption occur, because extracellular communication is intact. Overexpression of Bcl-2 in osteoblasts using 2.3 kb collagen type I alpha1 (COL1A1) promoter causes osteocyte apoptosis due to the severe reduction in the number of osteocyte processes, resulting in the disruption of both intracellular and extracellular communication systems. This mouse model unraveled osteocyte functions. Osteocytes negatively regulate bone mass by stimulating osteoclastogenesis and inhibiting osteoblast function in physiological condition. Osteocytes are responsible for bone loss in unloaded condition, and osteocytes augment their functions by further stimulating osteoclastogenesis and further inhibiting osteoblast function, at least partly, through the upregulation of receptor activator of nuclear factor-kappa B ligand

  14. Mouse Models for the Evaluation of Osteocyte Functions

    PubMed Central

    2014-01-01

    Osteocytes establish an extensive intracellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface. To examine the osteocyte function, several mouse models were established. To ablate osteocytes, osteocytes death was induced by diphtheria toxin. However, any types of osteocyte death result in necrosis, because dying osteocytes are not phagocytosed by scavengers. After the rupture of cytoplasmic membrane, immunostimulatory molecules are released from lacunae to bone surface through canaliculi, and stimulate macrophages. The stimulated macrophages produce interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-α), which are the most important proinflammatory cytokines triggering inflammatory bone loss. Therefore, the osteocyte ablation results in necrosis-induced severe osteoporosis. In conditional knockout mice of gap junction protein alpha-1 (GJA1), which encodes connexin 43 in Gap junction, using dentin matrix protein 1 (DMP1) Cre transgenic mice, osteocyte apoptosis and enhanced bone resorption occur, because extracellular communication is intact. Overexpression of Bcl-2 in osteoblasts using 2.3 kb collagen type I alpha1 (COL1A1) promoter causes osteocyte apoptosis due to the severe reduction in the number of osteocyte processes, resulting in the disruption of both intracellular and extracellular communication systems. This mouse model unraveled osteocyte functions. Osteocytes negatively regulate bone mass by stimulating osteoclastogenesis and inhibiting osteoblast function in physiological condition. Osteocytes are responsible for bone loss in unloaded condition, and osteocytes augment their functions by further stimulating osteoclastogenesis and further inhibiting osteoblast function, at least partly, through the upregulation of receptor activator of nuclear factor-kappa B ligand

  15. Evaluation of the Genetic and Nutritional Control of Obesity and Type 2 Diabetes in a Novel Mouse Model on Chromosome 7: An Insight into Insulin Signaling and Glucose Homeostasis

    SciTech Connect

    Nelson, S.; Dhar, M.

    2003-01-01

    Obesity is the main cause of type 2 diabetes, accounting for 90-95% of all diabetes cases in the US. Human obesity is a complex trait and can be studied using appropriate mouse models. A novel polygenic mouse model for studying the genetic and environmental contributions to and the physiological ramifications of obesity and related phenotypes is found in specific lines of mice bred and maintained at Oak Ridge National Laboratory. Heterozygous mice with a maternally inherited copy of two radiation-induced deletions in the p region of mouse chromosome 7, p23DFioD and p30PUb, have significantly greater body fat and show hyperinsulinemia compared to the wild-type. A single gene, Atp10c, maps to this critical region and codes for a putative aminophospholipid translocase. Biochemical and molecular studies were initiated to gain insight into obesity and glucose homeostasis in these animals and to study the biological role of Atp10c in creating these phenotypes. Glucose and insulin tolerance tests were standardized for the heterozygous p23DFioD and control mice on a custom-made diet containing 20% protein, 70% carbohydrate, and 10% fat (kcal). Atp10c expression profiles were also generated using Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR). Heterozygous p23DFioD animals showed insulin resistance after receiving a dose of either 0.375 or 0.75 U/kg Illetin R insulin. RT-PCR data also shows differences in Atp10c expression in the mutants versus control mice. Using these standardized biochemical assays, future studies will further the understanding of genetic and nutritional controls of glucose homeostasis and obesity in animal models and subsequently in human populations.

  16. 77 FR 24499 - Government-Owned Inventions; Availability for Licensing: Mouse Models

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-24

    ... Mouse Model for Respiratory System Studies Description of Mouse: FGFR4 knockout: Lung alveoli fail to... are viable but sickly. Potential Commercial Application: Model for the study of respiratory system and... biological systems including embryogenesis. TGF-beta ligands activate specific receptors, which interact...

  17. A New Model for Hendra Virus Encephalitis in the Mouse

    PubMed Central

    Dups, Johanna; Middleton, Deborah; Yamada, Manabu; Monaghan, Paul; Long, Fenella; Robinson, Rachel; Marsh, Glenn A.; Wang, Lin-Fa

    2012-01-01

    Hendra virus (HeV) infection in humans is characterized by an influenza like illness, which may progress to pneumonia or encephalitis and lead to death. The pathogenesis of HeV infection is poorly understood, and the lack of a mouse model has limited the opportunities for pathogenetic research. In this project we reassessed the role of mice as an animal model for HeV infection and found that mice are susceptible to HeV infection after intranasal exposure, with aged mice reliably developing encephalitic disease. We propose an anterograde route of neuroinvasion to the brain, possibly along olfactory nerves. This is supported by evidence for the development of encephalitis in the absence of viremia and the sequential distribution of viral antigen along pathways of olfaction in the brain of intranasally challenged animals. In our studies mice developed transient lower respiratory tract infection without progressing to viremia and systemic vasculitis that is common to other animal models. These studies report a new animal model of HeV encephalitis that will allow more detailed studies of the neuropathogenesis of HeV infection, particularly the mode of viral spread and possible sequestration within the central nervous system; investigation of mechanisms that moderate the development of viremia and systemic disease; and inform the development of improved treatment options for human patients. PMID:22808132

  18. A novel mouse model of advanced diabetic kidney disease.

    PubMed

    Thibodeau, Jean-Francois; Holterman, Chet E; Burger, Dylan; Read, Naomi C; Reudelhuber, Timothy L; Kennedy, Christopher R J

    2014-01-01

    Currently available rodent models exhibit characteristics of early diabetic nephropathy (DN) such as hyperfiltration, mesangial expansion, and albuminuria yet features of late DN (hypertension, GFR decline, tubulointerstitial fibrosis) are absent or require a significant time investment for full phenotype development. Accordingly, the aim of the present study was to develop a mouse model of advanced DN with hypertension superimposed (HD mice). Mice transgenic for human renin cDNA under the control of the transthyretin promoter (TTRhRen) were employed as a model of angiotensin-dependent hypertension. Diabetes was induced in TTRhRen mice through low dose streptozotocin (HD-STZ mice) or by intercrossing with OVE26 diabetic mice (HD-OVE mice). Both HD-STZ and HD-OVE mice displayed more pronounced increases in urinary albumin levels as compared with their diabetic littermates. Additionally, HD mice displayed renal hypertrophy, advanced glomerular scarring and evidence of tubulointerstitial fibrosis. Both HD-OVE and HD-STZ mice showed evidence of GFR decline as FITC-inulin clearance was decreased compared to hyperfiltering STZ and OVE mice. Taken together our results suggest that HD mice represent a robust model of type I DN that recapitulates key features of human disease which may be significant in studying the pathogenesis of DN and in the assessment of putative therapeutics.

  19. Eeyore: a novel mouse model of hereditary deafness.

    PubMed

    Miller, Kerry A; Williams, Louise H; Dahl, Hans-Henrik M; Manji, Shehnaaz S M

    2013-01-01

    Animal models that recapitulate human disease are proving to be an invaluable tool in the identification of novel disease-associated genes. These models can improve our understanding of the complex genetic mechanisms involved in disease and provide a basis to guide therapeutic strategies to combat these conditions. We have identified a novel mouse model of non-syndromic sensorineural hearing loss with linkage to a region on chromosome 18. Eeyore mutant mice have early onset progressive hearing impairment and show abnormal structure of the sensory epithelium from as early as 4 weeks of age. Ultrastructural and histological analyses show irregular hair cell structure and degeneration of the sensory hair bundles in the cochlea. The identification of new genes involved in hearing is central to understanding the complex genetic pathways involved in the hearing process and the loci at which these pathways are interrupted in people with a genetic hearing loss. We therefore discuss possible candidate genes within the linkage region identified in eeyore that may underlie the deafness phenotype in these mice. Eeyore provides a new model of hereditary sensorineural deafness and will be an important tool in the search for novel deafness genes.

  20. A knock-in mouse model of congenital erythropoietic porphyria.

    PubMed

    Ged, C; Mendez, M; Robert, E; Lalanne, M; Lamrissi-Garcia, I; Costet, P; Daniel, J Y; Dubus, P; Mazurier, F; Moreau-Gaudry, F; de Verneuil, H

    2006-01-01

    Congenital erythropoietic porphyria (CEP) is a recessive autosomal disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. The severity of the disease, the lack of specific treatment except for allogeneic bone marrow transplantation, and the knowledge of the molecular lesions are strong arguments for gene therapy. An animal model of CEP has been designed to evaluate the feasibility of retroviral gene transfer in hematopoietic stem cells. We have previously demonstrated that the knockout of the Uros gene is lethal in mice (Uros(del) model). This work describes the achievement of a knock-in model, which reproduces a mutation of the UROS gene responsible for a severe UROS deficiency in humans (P248Q missense mutant). Homozygous mice display erythrodontia, moderate photosensitivity, hepatosplenomegaly, and hemolytic anemia. Uroporphyrin (99% type I isomer) accumulates in urine. Total porphyrins are increased in erythrocytes and feces, while Uros enzymatic activity is below 1% of the normal level in the different tissues analyzed. These pathological findings closely mimic the CEP disease in humans and demonstrate that the Uros(mut248) mouse represents a suitable model of the human disease for pathophysiological, pharmaceutical, and therapeutic purposes.

  1. Mouse models for the study of human hair loss.

    PubMed

    Sundberg, J P; King, L E

    1996-10-01

    A comparison has been presented to illustrate many of the similarities in patterns of disease between mouse and human hair follicle diseases and how various mouse mutations can be used as research tools to investigate these observations. The powerful genetic tools available for investigating mouse mutations and human homologues will continue to result in many breakthroughs in the understanding of hair follicle biology and pathology. Many more mouse mutations are available than are described here. Information on these mutations fills books and computer databases, providing an unlimited resource.

  2. Altered CSMD1 Expression Alters Cocaine-Conditioned Place Preference: Mutual Support for a Complex Locus from Human and Mouse Models.

    PubMed

    Drgonova, Jana; Walther, Donna; Singhal, Sulabh; Johnson, Kennedy; Kessler, Brice; Troncoso, Juan; Uhl, George R

    2015-01-01

    The CUB and sushi multiple domains 1 (CSMD1) gene harbors signals provided by clusters of nearby SNPs with 10-2 > p > 10-8 associations in genome wide association (GWAS) studies of addiction-related phenotypes. A CSMD1 intron 3 SNP displays p < 10-8 association with schizophrenia and more modest associations with individual differences in performance on tests of cognitive abilities. CSDM1 encodes a cell adhesion molecule likely to influence development, connections and plasticity of brain circuits in which it is expressed. We tested association between CSMD1 genotypes and expression of its mRNA in postmortem human brains (n = 181). Expression of CSMD1 mRNA in human postmortem cerebral cortical samples differs 15-25%, in individuals with different alleles of simple sequence length and SNP polymorphisms located in the gene's third/fifth introns, providing nominal though not Bonferroni-corrected significance. These data support mice with altered CSMD1 expression as models for common human CSMD1 allelic variation. We tested baseline and/or cocaine-evoked addiction, emotion, motor and memory-related behaviors in +/- and -/- csmd1 knockout mice on mixed and on C57-backcrossed genetic backgrounds. Initial csmd1 knockout mice on mixed genetic backgrounds displayed a variety of coat colors and sizable individual differences in responses during behavioral testing. Backcrossed mice displayed uniform black coat colors. Cocaine conditioned place preference testing revealed significant influences of genotype (p = 0.02). Homozygote knockouts displayed poorer performance on aspects of the Morris water maze task. They displayed increased locomotion in some, though not all, environments. The combined data thus support roles for common level-of-expression CSMD1 variation in a drug reward phenotype relevant to addiction and in cognitive differences that might be relevant to schizophrenia. Mouse model results can complement data from human association findings of modest magnitude that

  3. Modelling clinical systemic lupus erythematosus: similarities, differences and success stories.

    PubMed

    Celhar, Teja; Fairhurst, Anna-Marie

    2016-12-24

    Mouse models of SLE have been indispensable tools to study disease pathogenesis, to identify genetic susceptibility loci and targets for drug development, and for preclinical testing of novel therapeutics. Recent insights into immunological mechanisms of disease progression have boosted a revival in SLE drug development. Despite promising results in mouse studies, many novel drugs have failed to meet clinical end points. This is probably because of the complexity of the disease, which is driven by polygenic predisposition and diverse environmental factors, resulting in a heterogeneous clinical presentation. Each mouse model recapitulates limited aspects of lupus, especially in terms of the mechanism underlying disease progression. The main mouse models have been fairly successful for the evaluation of broad-acting immunosuppressants. However, the advent of targeted therapeutics calls for a selection of the most appropriate model(s) for testing and, ultimately, identification of patients who will be most likely to respond.

  4. High plasticity of axonal pathology in Alzheimer's disease mouse models.

    PubMed

    Blazquez-Llorca, Lidia; Valero-Freitag, Susana; Rodrigues, Eva Ferreira; Merchán-Pérez, Ángel; Rodríguez, J Rodrigo; Dorostkar, Mario M; DeFelipe, Javier; Herms, Jochen

    2017-02-07

    Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer's disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.

  5. Iodine uptake and prostate cancer in the TRAMP mouse model.

    PubMed

    Olvera-Caltzontzin, Paloma; Delgado, Guadalupe; Aceves, Carmen; Anguiano, Brenda

    2013-11-08

    Iodine supplementation exerts antitumor effects in several types of cancer. Iodide (I⁻) and iodine (I₂) reduce cell proliferation and induce apoptosis in human prostate cancer cells (LNCaP and DU-145). Both chemical species decrease tumor growth in athymic mice xenografted with DU-145 cells. The aim of this study was to analyze the uptake and effects of iodine in a preclinical model of prostate cancer (transgenic adenocarcinoma of the mouse prostate [TRAMP] mice/SV40-TAG antigens), which develops cancer by 12 wks of age. ¹²⁵I⁻ and ¹²⁵I₂ uptake was analyzed in prostates from wild-type and TRAMP mice of 12 and 24 wks in the presence of perchlorate (inhibitor of the Na⁺/I⁻ symporter [NIS]). NIS expression was quantified by quantitative polymerase chain reaction (qPCR). Mice (6 wks old) were supplemented with 0.125 mg I⁻ plus 0.062 mg I₂/mouse/day for 12 or 24 wks. The weight of the genitourinary tract (GUT), the number of acini with lesions, cell proliferation (levels of proliferating cell nuclear antigen [PCNA] by immunohistochemistry), p53 and p21 expression (by qPCR) and apoptosis (relative amount of nucleosomes by enzyme-linked immunosorbent assay) were evaluated. In both age-groups, normal and tumoral prostates take up both forms of iodine, but only I⁻ uptake was blocked by perchlorate. Iodine supplementation prevented the overexpression of NIS in the TRAMP mice, but had no effect on the GUT weight, cell phenotype, proliferation or apoptosis. In TRAMP mice, iodine increased p53 expression but had no effect on p21 (a p53-dependent gene). Our data corroborate NIS involvement in I⁻ uptake and support the notion that another transporter mediates I₂ uptake. Iodine did not prevent cancer progression. This result could be explained by a strong inactivation of the p53 pathway by TAG antigens.

  6. Increased Glyburide Clearance in the Pregnant Mouse Model

    PubMed Central

    Zhou, Lin; Zhang, Yi; Hebert, Mary F.; Unadkat, Jashvant D.

    2010-01-01

    Glyburide (GLB) is an oral sulfonylurea, commonly used for the treatment of gestational diabetes mellitus. It has been reported that the clearance of GLB in pregnant women is significantly higher than that in nonpregnant women. The molecular mechanism by which pregnancy increases the clearance of GLB is not known, but it may be caused by increased CYP3A activity. Because liver tissue from pregnant women is not readily available, in the present study, we investigated the mechanism of such pregnancy-related changes in GLB disposition in a mouse model. We demonstrated that the systemic clearance of GLB in pregnant mice was increased approximately 2-fold (p < 0.01) compared with nonpregnant mice, a magnitude of change similar to that observed in the clinical study. Plasma protein binding of GLB in mice was not altered by pregnancy. The half-life of GLB depletion in hepatic S-9 fractions of pregnant mice was significantly shorter than that of nonpregnant mice. Moreover, GLB depletion was markedly inhibited by ketoconazole, a potent inhibitor of mouse Cyp3a, suggesting that GLB metabolism in mice is primarily mediated by hepatic Cyp3a. These data suggest that the increased systemic clearance of GLB in pregnant mice is likely caused by an increase in hepatic Cyp3a activity during pregnancy, and they provide a basis for further mechanistic understanding and analysis of pregnancy-induced alterations in the disposition of GLB and drugs that are predominantly and extensively metabolized by CYP3A/Cyp3a. PMID:20558597

  7. Mouse model of Timothy syndrome recapitulates triad of autistic traits.

    PubMed

    Bader, Patrick L; Faizi, Mehrdad; Kim, Leo H; Owen, Scott F; Tadross, Michael R; Alfa, Ronald W; Bett, Glenna C L; Tsien, Richard W; Rasmusson, Randall L; Shamloo, Mehrdad

    2011-09-13

    Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.

  8. Debridement increases survival in a mouse model of subcutaneous anthrax.

    PubMed

    Weiner, Zachary P; Boyer, Anne E; Gallegos-Candela, Maribel; Cardani, Amber N; Barr, John R; Glomski, Ian J

    2012-01-01

    Anthrax is caused by infection with Bacillus anthracis, a spore-forming gram-positive bacterium. A major virulence factor for B. anthracis is an immunomodulatory tripartite exotoxin that has been reported to alter immune cell chemotaxis and activation. It has been proposed that B. anthracis infections initiate through entry of spores into the regional draining lymph nodes where they germinate, grow, and disseminate systemically via the efferent lymphatics. If this model holds true, it would be predicted that surgical removal of infected tissues, debridement, would have little effect on the systemic dissemination of bacteria. This model was tested through the development of a mouse debridement model. It was found that removal of the site of subcutaneous infection in the ear increased the likelihood of survival and reduced the quantity of spores in the draining cervical lymph nodes (cLN). At the time of debridement 12 hours post-injection measurable levels of exotoxins were present in the ear, cLN, and serum, yet leukocytes within the cLN were activated; countering the concept that exotoxins inhibit the early inflammatory response to promote bacterial growth. We conclude that the initial entry of spores into the draining lymph node of cutaneous infections alone is not sufficient to cause systemic disease and that debridement should be considered as an adjunct to antibiotic therapy.

  9. A new mouse model of ADHD for medication development

    PubMed Central

    Majdak, Petra; Ossyra, John R.; Ossyra, Jessica M.; Cobert, Adam J.; Hofmann, Gabrielle C.; Tse, Stephen; Panozzo, Brent; Grogan, Elizabeth L.; Sorokina, Anastassia; Rhodes, Justin S.

    2016-01-01

    ADHD is a major societal problem with increasing incidence and a stagnant track record for treatment advances. A lack of appropriate animal models has partly contributed to the incremental advance of this field. Hence, our goal was to generate a novel mouse model that could be useful for ADHD medication development. We reasoned that hyperactivity is a core feature of ADHD that could easily be bred into a population, but to what extent other hallmark features of ADHD would appear as correlated responses was unknown. Hence, starting from a heterogeneous population, we applied within-family selection over 16 generations to produce a High-Active line, while simultaneously maintaining an unselected line to serve as the Control. We discovered that the High-Active line demonstrated motor impulsivity in two different versions of the Go/No-go test, which was ameliorated with a low dose of amphetamine, and further displayed hypoactivation of the prefrontal cortex and dysregulated cerebellar vermal activation as indexed by c-Fos immunohistochemical staining. We conclude that the High-Active line represents a valid model for the Hyperactive-Impulsive subtype of ADHD and therefore may be used in future studies to advance our understanding of the etiology of ADHD and screen novel compounds for its treatment. PMID:27996970

  10. A mouse model for an erythropoietin-deficiency anemia.

    PubMed

    Zeigler, Brandon M; Vajdos, Janis; Qin, Wenning; Loverro, Linda; Niss, Knut

    2010-01-01

    In mammals, the production of red blood cells is tightly regulated by the growth factor erythropoietin (EPO). Mice lacking a functional Epo gene are embryonic lethal, and studying erythropoiesis in EPO-deficient adult animals has therefore been limited. In order to obtain a preclinical model for an EPO-deficient anemia, we developed a mouse in which Epo can be silenced by Cre recombinase. After induction of Cre activity, Epo(KO/flox) mice experience a significant reduction of serum EPO levels and consequently develop a chronic, normocytic and normochromic anemia. Furthermore, compared with wild-type mice, Epo expression in Epo(KO/flox) mice is dramatically reduced in the kidney, and expression of a well-known target gene of EPO signaling, Bcl2l1, is reduced in the bone marrow. These observations are similar to the clinical display of anemia in patients with chronic kidney disease. In addition, during stress-induced erythropoiesis these mice display the same recovery rate as their heterozygous counterparts. Taken together, these results demonstrate that this model can serve as a valuable preclinical model for the anemia of EPO deficiency, as well as a tool for the study of stress-induced erythropoiesis during limiting conditions of EPO.

  11. Photodynamic therapy of oral Candida infection in a mouse model.

    PubMed

    Freire, Fernanda; Ferraresi, Cleber; Jorge, Antonio Olavo C; Hamblin, Michael R

    2016-06-01

    Species of the fungal genus Candida, can cause oral candidiasis especially in immunosuppressed patients. Many studies have investigated the use of photodynamic therapy (PDT) to kill fungi in vitro, but this approach has seldom been reported in animal models of infection. This study investigated the effects of PDT on Candida albicans as biofilms grown in vitro and also in an immunosuppressed mouse model of oral candidiasis infection. We used a luciferase-expressing strain that allowed non-invasive monitoring of the infection by bioluminescence imaging. The phenothiazinium salts, methylene blue (MB) and new methylene blue (NMB) were used as photosensitizers (PS), combined or not with potassium iodide (KI), and red laser (660nm) at four different light doses (10J, 20J, 40J and 60J). The best in vitro log reduction of CFU/ml on biofilm grown cells was: MB plus KI with 40J (2.31 log; p<0.001); and NMB without KI with 60J (1.77 log; p<0.001). These conditions were chosen for treating the in vivo model of oral Candida infection. After 5days of treatment the disease was practically eradicated, especially using MB plus KI with 40J. This study suggests that KI can potentiate PDT of fungal infection using MB (but not NMB) and could be a promising new approach for the treatment of oral candidiasis.

  12. [Mouse models of K-ras-initiated oncogenesis].

    PubMed

    Barrière, C; Marjou, F El; Louvard, D; Robine, S

    2009-12-01

    Activating mutations of the oncogene K-ras are found in one third of all human cancers. Much of our knowledge on K-ras signal transduction and its influence on tumor initiation and progression come from in vitro studies with cell lines. However, mouse models of human cancer allow a much more faithful recapitulation of the human disease, and the in vivo perspective is crucial for our understanding of neoplasia. In recent years, several new murine models for K-ras-induced tumorigenesis have been described. They allow new insights into the specific role that oncogenic K-ras proteins play in different solid tumors, and they permit the molecular dissection of the pathways that are initiated by somatic mutations in subsets of cells. Key advances have been made by the use of tissue-specific and inducible control of expression, which is achieved by the Cre/loxP technology or the tetracycline system. From these sophisticated models, a common picture emerges: the effects of K-ras on tumor initiation depend strongly on the cellular context, and different tissues vary in their susceptibility to K-ras transformation.

  13. Indirubin Treatment of Lipopolysaccharide-Induced Mastitis in a Mouse Model and Activity in Mouse Mammary Epithelial Cells

    PubMed Central

    Lai, Jin-lun; Liu, Yu-hui; Peng, Yong-chong; Ge, Pan; He, Chen-fei; Liu, Chang; Chen, Ying-yu; Guo, Ai-zhen

    2017-01-01

    Indirubin is a Chinese medicine extracted from indigo and known to be effective for treating chronic myelogenous leukemia, neoplasia, and inflammatory disease. This study evaluated the in vivo anti-inflammatory activity of indirubin in a lipopolysaccharide- (LPS-) induced mouse mastitis model. The indirubin mechanism and targets were evaluated in vitro in mouse mammary epithelial cells. In the mouse model, indirubin significantly attenuated the severity of inflammatory lesions, edema, inflammatory hyperemia, milk stasis and local tissue necrosis, and neutrophil infiltration. Indirubin significantly decreased myeloperoxidase activity and downregulated the production of tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 caused by LPS. In vitro, indirubin inhibited LPS-stimulated expression of proinflammatory cytokines in a dose-dependent manner. It also downregulated LPS-induced toll-like receptor 4 (TLR4) expression and inhibited phosphorylation of LPS-induced nuclear transcription factor-kappa B (NF-κB) P65 protein and inhibitor of kappa B. In addition to its effect on the NF-κB signaling pathway, indirubin suppressed the mitogen-activated protein kinase (MAPK) signaling by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK), P38, and c-jun NH2-terminal kinase (JNK). Indirubin improved LPS-induced mouse mastitis by suppressing TLR4 and downstream NF-κB and MAPK pathway inflammatory signals and might be a potential treatment of mastitis and other inflammatory diseases. PMID:28255203

  14. IMQ Induced K14-VEGF Mouse: A Stable and Long-Term Mouse Model of Psoriasis-Like Inflammation

    PubMed Central

    Wang, Xuguo; Sun, Jun; Hu, JinHong

    2015-01-01

    An imiquimod (IMQ) induced wild type (WT) mouse can mimic some features of psoriasis, such as thickened skin, abnormal keratinocyte-related proteins, infiltration of inflammatory cells and pro-inflammatory cytokines. This model is a prevalent model that is widely used in the study of psoriasis. However, skin inflammation decreases during the eighth day when IMQ is given to WT mice, which may result in false results when evaluating the pharmacodynamics effects of a drug. To extend the timeliness and inherit the advantages of this model, we applied IMQ to the skin of 8-week-old homozygous K14-VEGF mice to investigate whether IMQ can prolong mice ear inflammation. In our experiments, we found that, compared to the IMQ induced WT mice model, the IMQ induced K14-VEGF mice have serious skin inflammation, even on the fourteenth day. We also evaluated the stability of skin inflammation at days 8, 10, and 13, and the inflammatory situation remained stable in the skin. This research intends to improve the existing model, and we hypothesize that the IMQ induced K14-VEGF mouse will become a practical mouse model in psoriasis research. PMID:26691862

  15. HUPO BPP Workshop on Mouse Models for Neurodegeneration--Choosing the right models.

    PubMed

    Hamacher, Michael; Marcus, Katrin; Stephan, Christian; van Hall, Andre; Meyer, Helmut E

    2005-09-01

    The HUPO Brain Proteome Project met during the 4th Dutch Endo-Neuro-Psycho Meeting in Doorwerth, The Netherlands, on June 1, 2005, in order to discuss appropriate (mouse) models for neurodegenerative diseases as well as to conceptualise sophisticated proteomics analyses strategies. Here, the topics of the meeting are summarised.

  16. Single and Multiple Gene Manipulations in Mouse Models of Human Cancer

    PubMed Central

    Lehman, Heather L; Stairs, Douglas B

    2015-01-01

    Mouse models of human cancer play a critical role in understanding the molecular and cellular mechanisms of tumorigenesis. Advances continue to be made in modeling human disease in a mouse, though the relevance of a mouse model often relies on how closely it is able to mimic the histologic, molecular, and physiologic characteristics of the respective human cancer. A classic use of a genetically engineered mouse in studying cancer is through the overexpression or deletion of a gene. However, the manipulation of a single gene often falls short of mimicking all the characteristics of the carcinoma in humans; thus a multiple gene approach is needed. Here we review genetic mouse models of cancers and their abilities to recapitulate human carcinoma with single versus combinatorial approaches with genes commonly involved in cancer. PMID:26380553

  17. The mouse gut microbiome revisited: From complex diversity to model ecosystems.

    PubMed

    Clavel, Thomas; Lagkouvardos, Ilias; Blaut, Michael; Stecher, Bärbel

    2016-08-01

    Laboratory mice are the most commonly used animal model in translational medical research. In recent years, the impact of the gut microbiota (i.e. communities of microorganisms in the intestine) on host physiology and the onset of diseases, including metabolic and neuronal disorders, cancers, gastrointestinal infections and chronic inflammation, became a focal point of interest. There is abundant evidence that mouse phenotypes in disease models vary greatly between animal facilities or commercial providers, and that this variation is associated with differences in the microbiota. Hence, there is a clear discrepancy between the widespread use of mouse models in research and the patchwork knowledge on the mouse gut microbiome. In the present manuscript, we summarize data pertaining to the diversity and functions of the mouse gut microbiota, review existing work on gnotobiotic mouse models, and discuss challenges and opportunities for current and future research in the field.

  18. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

    PubMed

    Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

    2015-07-15

    Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path

  19. Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

    PubMed Central

    Tran, Nicholas M.; Zhang, Alan; Zhang, Xiaodong; Huecker, Julie B.; Hennig, Anne K.; Chen, Shiming

    2014-01-01

    Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of

  20. The mouse genome database: genotypes, phenotypes, and models of human disease.

    PubMed

    Bult, Carol J; Eppig, Janan T; Blake, Judith A; Kadin, James A; Richardson, Joel E

    2013-01-01

    The laboratory mouse is the premier animal model for studying human biology because all life stages can be accessed experimentally, a completely sequenced reference genome is publicly available and there exists a myriad of genomic tools for comparative and experimental research. In the current era of genome scale, data-driven biomedical research, the integration of genetic, genomic and biological data are essential for realizing the full potential of the mouse as an experimental model. The Mouse Genome Database (MGD; http://www.informatics.jax.org), the community model organism database for the laboratory mouse, is designed to facilitate the use of the laboratory mouse as a model system for understanding human biology and disease. To achieve this goal, MGD integrates genetic and genomic data related to the functional and phenotypic characterization of mouse genes and alleles and serves as a comprehensive catalog for mouse models of human disease. Recent enhancements to MGD include the addition of human ortholog details to mouse Gene Detail pages, the inclusion of microRNA knockouts to MGD's catalog of alleles and phenotypes, the addition of video clips to phenotype images, providing access to genotype and phenotype data associated with quantitative trait loci (QTL) and improvements to the layout and display of Gene Ontology annotations.

  1. SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis

    PubMed Central

    Fleet, Tiffany; Zhang, Bin; Lin, Fumin; Zhu, Bokai; Dasgupta, Subhamoy; Stashi, Erin; Tackett, Bryan; Thevananther, Sundararajah; Rajapakshe, Kimal I.; Gonzales, Naomi; Dean, Adam; Mao, Jianqiang; Timchenko, Nikolai; Malovannaya, Anna; Qin, Jun; Coarfa, Cristian; DeMayo, Francesco; Dacso, Clifford C.; Foulds, Charles E.; O’Malley, Bert W.; York, Brian

    2015-01-01

    Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation. PMID:26487680

  2. Polygenic phenotypic plasticity moderates the effects of severe childhood abuse on depressive symptom severity in adulthood: A 5-year prospective cohort study.

    PubMed

    Bousman, Chad A; Gunn, Jane M; Potiriadis, Maria; Everall, Ian P

    2017-02-01

    Objective To test the phenotypic plasticity framework using a polygenic approach in a prospective depression cohort of primary care attendees with and without histories of severe childhood abuse. Methods Depressive symptoms were assessed at baseline and annually for 5 years post-baseline using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9) among 288 adult primary care attendees. Twelve polymorphisms in nine genes were genotyped and polygenic phenotypic plasticity allelic load (PAL) calculated. Linear mixed models assessed differences in depressive symptom severity over the 5-year follow-up period by PAL and history of severe childhood abuse. Results A higher PAL conferred greater depressive symptom severity among those with a history of severe childhood abuse but conferred significantly lower symptom severity among those without this history. Importantly, this interaction withstood adjustments for important covariates (e.g., antidepressant use, comorbid anxiety) and was stable over the 5 years of observation. Conclusions Aligned with the phenotypic plasticity framework, depressive symptom severity was dependent on the interaction between PAL and history of severe childhood abuse in a "for better and for worse" manner. Measures of polygenic phenotypic plasticity, such as ours, may serve as a trait marker of sensitivity to negative and potentially positive environmental influences.

  3. Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex

    PubMed Central

    Guo, Yanan; Dreier, John R.; Cao, Juxiang; Du, Heng; Granter, Scott R.; Kwiatkowski, David J.

    2016-01-01

    Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis. They did develop a prominent skin phenotype with marked thickening of the dermis with accumulation of mast cells, that was minimally responsive to systemic rapamycin therapy, and was quite different from the pathology seen in human TSC skin lesions. Recombination and loss of Tsc1 was demonstrated in skin fibroblasts in vivo and in cultured skin fibroblasts. Loss of Tsc1 in fibroblasts in mice does not lead to a model of angiomyolipoma or lymphangioleiomyomatosis. PMID:27907099

  4. Breathing abnormalities in a female mouse model of Rett syndrome.

    PubMed

    Johnson, Christopher M; Cui, Ningren; Zhong, Weiwei; Oginsky, Max F; Jiang, Chun

    2015-09-01

    Rett syndrome (RTT) is a female neurodevelopmental disease with breathing abnormalities. To understand whether breathing defects occur in the early lives of a group of female Mecp2(+/-) mice, a mouse model of RTT, and what percentage of mice shows RTT-like breathing abnormality, breathing activity was measured by plethysmography in conscious mice. Breathing frequency variation and central apnea in a group of Mecp2(+/-) females displayed a distribution pattern similar to Mecp2(-/Y) males, while the rest resembled the wild-type mice. Similar results were obtained using the k-mean clustering statistics analysis. With two independent methods, about 20% of female Mecp2(+/-) mice showed RTT-like breathing abnormalities that began as early as 3 weeks of age in the Mecp2(+/-) mice, and were suppressed with 3% CO2. The finding that only a small proportion of Mecp2(+/-) mice develops RTT-like breathing abnormalities suggests incomplete allele inactivation in the RTT-model Mecp2(+/-) mice.

  5. Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model.

    PubMed

    Liu, Chengcheng; Janke, Laura J; Kawedia, Jitesh D; Ramsey, Laura B; Cai, Xiangjun; Mattano, Leonard A; Boyd, Kelli L; Funk, Amy J; Relling, Mary V

    2016-01-01

    Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.

  6. Implantation of Inferior Vena Cava Interposition Graft in Mouse Model

    PubMed Central

    Lee, Yong-Ung; Yi, Tai; Tara, Shuhei; Lee, Avione Y.; Hibino, Narutoshi; Shinoka, Toshiharu; Breuer, Christopher K.

    2014-01-01

    Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are often used for reconstructive surgery to treat congenital cardiac anomalies. The long-term clinical results showed excellent patency rates, however, with significant incidence of stenosis. To investigate the cellular and molecular mechanisms of vascular neotissue formation and prevent stenosis development in tissue engineered vascular grafts (TEVGs), we developed a mouse model of the graft with approximately 1 mm internal diameter. First, the TEVGs were assembled from biodegradable tubular scaffolds fabricated from a polyglycolic acid nonwoven felt mesh coated with ε-caprolactone and L-lactide copolymer. The scaffolds were then placed in a lyophilizer, vacuumed for 24 hr, and stored in a desiccator until cell seeding. Second, bone marrow was collected from donor mice and mononuclear cells were isolated by density gradient centrifugation. Third, approximately one million cells were seeded on a scaffold and incubated O/N. Finally, the seeded scaffolds were then implanted as infrarenal vena cava interposition grafts in C57BL/6 mice. The implanted grafts demonstrated excellent patency (>90%) without evidence of thromboembolic complications or aneurysmal formation. This murine model will aid us in understanding and quantifying the cellular and molecular mechanisms of neotissue formation in the TEVG. PMID:24961688

  7. Mouse Model of Respiratory Tract Infection Induced by Waddlia chondrophila

    PubMed Central

    Pilloux, Ludovic; LeRoy, Didier; Brunel, Christophe

    2016-01-01

    Waddlia chondrophila, an obligate intracellular bacterium belonging to the Chlamydiales order, is considered as an emerging pathogen. Some clinical studies highlighted a possible role of W. chondrophila in bronchiolitis, pneumonia and miscarriage. This pathogenic potential is further supported by the ability of W. chondrophila to infect and replicate within human pneumocytes, macrophages and endometrial cells. Considering that W. chondrophila might be a causative agent of respiratory tract infection, we developed a mouse model of respiratory tract infection to get insight into the pathogenesis of W. chondrophila. Following intranasal inoculation of 2 x 108 W. chondrophila, mice lost up to 40% of their body weight, and succumbed rapidly from infection with a death rate reaching 50% at day 4 post-inoculation. Bacterial loads, estimated by qPCR, increased from day 0 to day 3 post-infection and decreased thereafter in surviving mice. Bacterial growth was confirmed by detecting dividing bacteria using electron microscopy, and living bacteria were isolated from lungs 14 days post-infection. Immunohistochemistry and histopathology of infected lungs revealed the presence of bacteria associated with pneumonia characterized by an important multifocal inflammation. The high inflammatory score in the lungs was associated with the presence of pro-inflammatory cytokines in both serum and lungs at day 3 post-infection. This animal model supports the role of W. chondrophila as an agent of respiratory tract infection, and will help understanding the pathogenesis of this strict intracellular bacterium. PMID:26950066

  8. The gut microbiota in mouse models of inflammatory bowel disease

    PubMed Central

    Gkouskou, Kalliopi K.; Deligianni, Chrysoula; Tsatsanis, Christos; Eliopoulos, Aristides G.

    2014-01-01

    The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD. PMID:24616886

  9. Biomarker Discovery and Redundancy Reduction towards Classification using a Multi-factorial MALDI-TOF MS T2DM Mouse Model Dataset

    PubMed Central

    2011-01-01

    Background Diabetes like many diseases and biological processes is not mono-causal. On the one hand multi-factorial studies with complex experimental design are required for its comprehensive analysis. On the other hand, the data from these studies often include a substantial amount of redundancy such as proteins that are typically represented by a multitude of peptides. Coping simultaneously with both complexities (experimental and technological) makes data analysis a challenge for Bioinformatics. Results We present a comprehensive work-flow tailored for analyzing complex data including data from multi-factorial studies. The developed approach aims at revealing effects caused by a distinct combination of experimental factors, in our case genotype and diet. Applying the developed work-flow to the analysis of an established polygenic mouse model for diet-induced type 2 diabetes, we found peptides with significant fold changes exclusively for the combination of a particular strain and diet. Exploitation of redundancy enables the visualization of peptide correlation and provides a natural way of feature selection for classification and prediction. Classification based on the features selected using our approach performs similar to classifications based on more complex feature selection methods. Conclusions The combination of ANOVA and redundancy exploitation allows for identification of biomarker candidates in multi-dimensional MALDI-TOF MS profiling studies with complex experimental design. With respect to feature selection our method provides a fast and intuitive alternative to global optimization strategies with comparable performance. The method is implemented in R and the scripts are available by contacting the corresponding author. PMID:21554713

  10. Mouse Models of Human Bladder Cancer as a Tool for Drug Discovery

    PubMed Central

    Seager, Catherine; Puzio-Kuter, Anna M.; Cordon-Cardo, Carlos; McKiernan, James; Abate-Shen, Cory

    2010-01-01

    Muscle-invasive bladder cancer is a deadly condition in dire need of effective new treatments. This unit contains a description of mouse models suitable for the evaluation of potential new therapies. Included is a genetically engineered mouse model of bladder cancer generated by the delivery of an adenovirus expressing Cre recombinase into the bladder lumen. Also described is an orthotopic mouse model created by the instillation of human bladder tumor cells into the bladder lumen of immune deficient mice. Protocols are also provided on the use of these models for the preclinical evaluation of new chemical entities, with mTOR inhibitors shown as an example. PMID:22294368

  11. Immunocompromised and immunocompetent mouse models for head and neck squamous cell carcinoma

    PubMed Central

    Lei, Zhen-ge; Ren, Xiao-hua; Wang, Sha-sha; Liang, Xin-hua; Tang, Ya-ling

    2016-01-01

    Mouse models can closely mimic human oral squamous epithelial carcinogenesis, greatly expand the in vivo research possibilities, and play a critical role in the development of diagnosis, monitoring, and treatment of head and neck squamous cell carcinoma. With the development of the recent research on the contribution of immunity/inflammation to cancer initiation and progression, mouse models have been divided into two categories, namely, immunocompromised and immunocompetent mouse models. And thus, this paper will review these two kinds of models applied in head and neck squamous cell carcinoma to provide a platform to understand the complicated histological, molecular, and genetic changes of oral squamous epithelial tumorigenesis. PMID:26869799

  12. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.

    PubMed

    Grimbacher, Bodo; Warnatz, Klaus; Yong, Patrick F K; Korganow, Anne-Sophie; Peter, Hans-Hartmut

    2016-01-01

    Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.

  13. Mouse models of osteoarthritis: surgical model of posttraumatic osteoarthritis induced by destabilization of the medial meniscus.

    PubMed

    Culley, Kirsty L; Dragomir, Cecilia L; Chang, Jun; Wondimu, Elisabeth B; Coico, Jonathan; Plumb, Darren A; Otero, Miguel; Goldring, Mary B

    2015-01-01

    The surgical model of destabilization of the medial meniscus (DMM) has become a gold standard for studying the onset and progression of posttraumatic osteoarthritis (OA). The DMM model mimics clinical meniscal injury, a known predisposing factor for the development of human OA, and permits the study of structural and biological changes over the course of the disease. In addition, when applied to genetically modified or engineered mouse models, this surgical procedure permits dissection of the relative contribution of a given gene to OA initiation and/or progression. This chapter describes the requirements for the surgical induction of OA in mouse models, and provides guidelines and tools for the subsequent histological, immunohistochemical, and molecular analyses. Methods for the assessment of the contributions of selected genes in genetically modified strains are also provided.

  14. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    DTIC Science & Technology

    2015-10-01

    Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING...SUBTITLE Developiing Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER Carcinoma Using Genetically Engineered Mouse Models and 5b...biomarkers. 15. SUBJECT TERMS Small cell lung cancer (SCLC), Genetically engineered mouse model (GEMM), BH3 mimetic, TORC inhibitor, Apoptosis

  15. Inflammation Oxidative Stress and Preneoplasia in a Mouse Model of Chronic Bacterial Prostatitis

    DTIC Science & Technology

    2005-09-01

    2003;361:955-64. 31. Hopkins WJ, Gendron-Fitzpatrick A, Balish E, Uehling DT. Escherichia coli urinary tract infection in genetically distinct mouse...strains: Time-course and host responses to infection. Infect Immun. 1998;66:2798-2802. 32. Hopkins WJ. Mouse model of ascending urinary tract infection . Chapter

  16. Structure guided homology model based design and engineering of mouse antibodies for humanization.

    PubMed

    Kurella, Vinodh B; Gali, Reddy

    2014-01-01

    No universal strategy exists for humanizing mouse antibodies, and most approaches are based on primary sequence alignment and grafting. Although this strategy theoretically decreases the immunogenicity of mouse antibodies, it neither addresses conformational changes nor steric clashes that arise due to grafting of human germline frameworks to accommodate mouse CDR regions. To address these issues, we created and tested a structure-based biologic design approach using a de novo homology model to aid in the humanization of 17 unique mouse antibodies. Our approach included building a structure-based de novo homology model from the primary mouse antibody sequence, mutation of the mouse framework residues to the closest human germline sequence and energy minimization by simulated annealing on the humanized homology model. Certain residues displayed force field errors and revealed steric clashes upon closer examination. Therefore, further mutations were introduced to rationally correct these errors. In conclusion, use of de novo antibody homology modeling together with simulated annealing improved the ability to predict conformational and steric clashes that may arise due to conversion of a mouse antibody into the humanized form and would prevent its neutralization when administered in vivo. This design provides a robust path towards the development of a universal strategy for humanization of mouse antibodies using computationally derived antibody homologous structures.

  17. High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

    PubMed Central

    Hamshere, Marian L.; Langley, Kate; Martin, Joanna; Agha, Sharifah Shameem; Stergiakouli, Evangelia; Anney, Richard J.L.; Buitelaar, Jan; Faraone, Stephen V.; Lesch, Klaus-Peter; Neale, Benjamin M.; Franke, Barbara; Sonuga-Barke, Edmund; Asherson, Philip; Merwood, Andrew; Kuntsi, Jonna; Medland, Sarah E.; Ripke, Stephan; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Roeyers, Herbert; Biederman, Joseph; Doyle, Alysa E.; Hakonarson, Hakon; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; McGough, James J.; Kent, Lindsey; Williams, Nigel; Owen, Michael J.; Holmans, Peter

    2013-01-01

    Objective Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. Conclusions Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity. PMID:23599091

  18. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology.

    PubMed

    McCarroll, Steven A; Hyman, Steven E

    2013-10-30

    Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.

  19. Innovations in phenotyping of mouse models in the German Mouse Clinic.

    PubMed

    Fuchs, Helmut; Gailus-Durner, Valérie; Neschen, Susanne; Adler, Thure; Afonso, Luciana Caminha; Aguilar-Pimentel, Juan Antonio; Becker, Lore; Bohla, Alexander; Calzada-Wack, Julia; Cohrs, Christian; Dewert, Anna; Fridrich, Barbara; Garrett, Lillian; Glasl, Lisa; Götz, Alexander; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Hurt, Anja; Janas, Eva; Janik, Dirk; Kahle, Melanie; Kistler, Martin; Klein-Rodewald, Tanja; Lengger, Christoph; Ludwig, Tonia; Maier, Holger; Marschall, Susan; Micklich, Kateryna; Möller, Gabriele; Naton, Beatrix; Prehn, Cornelia; Puk, Oliver; Rácz, Ildikó; Räss, Michael; Rathkolb, Birgit; Rozman, Jan; Scheerer, Markus; Schiller, Evelyn; Schrewe, Anja; Steinkamp, Ralph; Stöger, Claudia; Sun, Minxuan; Szymczak, Wilfried; Treise, Irina; Vargas Panesso, Ingrid Liliana; Vernaleken, Alexandra M; Willershäuser, Monja; Wolff-Muscate, Annemarie; Zeh, Ramona; Adamski, Jerzy; Beckers, Johannes; Bekeredjian, Raffi; Busch, Dirk H; Eickelberg, Oliver; Favor, Jack; Graw, Jochen; Höfler, Heinz; Höschen, Christoph; Katus, Hugo; Klingenspor, Martin; Klopstock, Thomas; Neff, Frauke; Ollert, Markus; Schulz, Holger; Stöger, Tobias; Wolf, Eckhard; Wurst, Wolfgang; Yildirim, Ali Önder; Zimmer, Andreas; Hrabě de Angelis, Martin

    2012-10-01

    Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).

  20. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.

    PubMed

    Srinivasan, Sudha; Hanes, Martha A; Dickens, Tayeashai; Porteous, Mary E M; Oh, S Paul; Hale, Laura P; Marchuk, Douglas A

    2003-03-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant disorder characterized by the age-dependent development of focal arteriovenous malformations and telangiectases. HHT type 2 is caused by loss of function mutations in activin receptor-like kinase 1 (ACVRL1 or ALK1). However, the factors that initiate lesion formation and those that influence disease progression remain unknown. Because heterozygous mice contain the appropriate genotype for an animal model of this disorder, mice heterozygous for a loss-of-function mutation in Acvrl1 were carefully examined for an HHT-like phenotype. These mice developed age-dependent vascular lesions in the skin, extremities, oral cavity and in the internal organs (lung, liver, intestine, spleen and brain), similar to those seen in HHT patients. Major histopathological features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage and fibrosis. Similar to HHT patients, the mice also exhibited gastrointestinal bleeding, as evidenced by positive fecal occult blood tests. An Acvrl1(+/-) mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. The similarity of affected organs, age-dependent penetrance, histological similarity of the lesions and recapitulation of a secondary phenotype suggest that the Acvrl1(+/-) mice are an appropriate animal model for the identification of additional genetic and environmental factors that cause pathology in HHT type 2 patients. In addition, studies utilizing this animal model can yield valuable information on the role of ALK1 in maintenance of adult vascular architecture including arteriovenous identity.

  1. [The Function of REM Sleep: Implications from Transgenic Mouse Models].

    PubMed

    Kashiwagi, Mitsuaki; Hayashi, Yu

    2016-10-01

    Our sleep is composed of rapid eye movement (REM) sleep and non-REM (NREM) sleep. REM sleep is the major source of dreams, whereas synchronous cortical oscillations, called slow waves, are observed during NREM sleep. Both stages are unique to certain vertebrate species, and therefore, REM and NREM sleep are thought to be involved in higher-order brain functions. While several studies have revealed the importance of NREM sleep in growth hormone secretion, memory consolidation and brain metabolite clearance, the functions of REM sleep are currently almost totally unknown. REM sleep functions cannot be easily indicated from classical REM sleep deprivation experiments, where animals are forced to wake up whenever they enter REM sleep, because such experiments produce extreme stress due to the stimuli and because REM sleep is under strong homeostatic regulation. To overcome these issues, we developed a novel transgenic mouse model in which REM sleep can be manipulated. Using these mice, we found that REM sleep enhances slow wave activity during the subsequent NREM sleep. Slow wave activity is known to contribute to memory consolidation and synaptic plasticity. Thus, REM sleep might be involved in higher-order brain functions through its role in enhancing slow wave activity.

  2. Assessing Functional Performance in the Mdx Mouse Model

    PubMed Central

    Aartsma-Rus, Annemieke; van Putten, Maaike

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories. PMID:24747372

  3. RANKL, osteopontin, and osteoclast homeostasis in a hyperocclusion mouse model

    SciTech Connect

    Walker, Cameron G.; Ito, Yoshihiro; Dangaria, Smit; Luan, Xianghong; Diekwisch, Thomas G.H.

    2009-10-21

    The biological mechanisms that maintain the position of teeth in their sockets establish a dynamic equilibrium between bone resorption and apposition. In order to reveal some of the dynamics involved in the tissue responses towards occlusal forces on periodontal ligament (PDL) and alveolar bone homeostasis, we developed the first mouse model of hyperocclusion. Swiss-Webster mice were kept in hyperocclusion for 0, 3, 6, and 9 d. Morphological and histological changes in the periodontium were assessed using micro-computed tomography (micro-CT) and ground sections with fluorescent detection of vital dye labels. Sections were stained for tartrate-resistant acid phosphatase, and the expression of receptor activator of nuclear factor-{kappa}B ligand (RANKL) and osteopontin (OPN) was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). Traumatic occlusion resulted in enamel surface abrasion, inhibition of alveolar bone apposition, significant formation of osteoclasts at 3, 6 and 9 d, and upregulation of OPN and RANKL. Data from this study suggest that both OPN and RANKL contribute to the stimulation of bone resorption in the hyperocclusive state. In addition, we propose that the inhibition of alveolar bone apposition by occlusal forces is an important mechanism for the control of occlusal height that might work in synergy with RANKL-induced bone resorption to maintain normal occlusion.

  4. Efficacy of Enrofloxacin in a Mouse Model of Sepsis

    PubMed Central

    Bandyopadhyay, Sheila; Francis, Kevin P; Papich, Mark G; Karolewski, Brian; Hod, Eldad A; Prestia, Kevin A

    2014-01-01

    We examined the efficacy of enrofloxacin administered by 2 different routes in a mouse model of sepsis. Male CD1 mice were infected with a bioluminescent strain of enteropathogenic Escherichia coli and treated with enrofloxacin either by injection or in drinking water. Peak serum levels were evaluated by using HPLC. Mice were monitored for signs of clinical disease, and infections were monitored by using bioluminescence imaging. Serum levels of enrofloxacin and the active metabolite ciprofloxacin were greater in the group treated by injection than in controls or the groups treated by administration in drinking water. Survival of the group treated with enrofloxacin injection was greater than that of controls and groups treated with enrofloxacin in the drinking water. Bioluminescence in the group treated with enrofloxacin injection was less than that in the groups treated with oral administration at 12 h and in the groups treated orally and the control group at 16 h. According to these findings, we recommend the use of injectable enrofloxacin at 5 mg/kg SC for mice with systemic infections. PMID:25199094

  5. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    PubMed Central

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  6. A Mouse Model of Fatigue Induced by Peripheral Irradiation.

    PubMed

    Wolff, Brian S; Renner, Michael A; Springer, Danielle A; Saligan, Leorey N

    2017-03-17

    Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue.

  7. Bone metabolism: a note on the significance of mouse models.

    PubMed

    Raska, O; Bernásková, K; Raska, I

    2009-01-01

    This minireview briefly surveys the complexity of regulations governing the bone metabolism. The impact of clinical studies devoted to osteoporosis is briefly summarized and the emphasis is put on the significance of experimental mouse models based on an extensive use of genetically modified animals. Despite possible arising drawbacks, the studies in mice are of prime importance for expanding our knowledge on bone metabolism. With respect to human physiology and medicine, one should be always aware of possible limitations as the experimental results may not be, or may be only to some extent, transposed to humans. If applicable to humans, results obtained in mice provide new clues for assessing unforeseen treatment strategies for patients. A recent publication representing in our opinion the important breakthrough in the field of bone metabolism in mice is commented in detail. It provides an evidence that skeleton is endocrine organ that affects energy metabolism and osteocalcin, a protein specifically synthesized and secreted by osteoblasts, is a hormone involved. If confirmed by other groups and applicable to humans, this study provides the awaited connection of long duration between bone disorders on one hand and obesity and diabetes on the other.

  8. A Metastatic Mouse Model Identifies Genes That Regulate Neuroblastoma Metastasis.

    PubMed

    Seong, Bo Kyung A; Fathers, Kelly E; Hallett, Robin; Yung, Christina K; Stein, Lincoln D; Mouaaz, Samar; Kee, Lynn; Hawkins, Cynthia E; Irwin, Meredith S; Kaplan, David R

    2017-02-01

    Metastatic relapse is the major cause of death in pediatric neuroblastoma, where there remains a lack of therapies to target this stage of disease. To understand the molecular mechanisms mediating neuroblastoma metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate malignant cell subpopulations with a higher propensity for metastasis to bone and the central nervous system. Gene expression profiling revealed primary and metastatic cells as two distinct cell populations defined by differential expression of 412 genes and of multiple pathways, including CADM1, SPHK1, and YAP/TAZ, whose expression independently predicted survival. In the metastatic subpopulations, a gene signature was defined (MET-75) that predicted survival of neuroblastoma patients with metastatic disease. Mechanistic investigations demonstrated causal roles for CADM1, SPHK1, and YAP/TAZ in mediating metastatic phenotypes in vitro and in vivo Notably, pharmacologic targeting of SPHK1 or YAP/TAZ was sufficient to inhibit neuroblastoma metastasis in vivo Overall, we identify gene expression signatures and candidate therapeutics that could improve the treatment of metastatic neuroblastoma. Cancer Res; 77(3); 696-706. ©2017 AACR.

  9. What have we learned from brucellosis in the mouse model?

    PubMed Central

    2012-01-01

    tested in mice by determining splenic Brucella numbers after challenging with appropriate virulent brucellae doses at precise post-vaccination times. Since most live or killed Brucella vaccines provide some protection in mice, controls immunized with reference vaccines (S19 or Rev1) are critical. Finally, mice have been successfully used to evaluate brucellosis therapies. It is concluded that, when used properly, the mouse is a valuable brucellosis model. PMID:22500859

  10. Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia.

    PubMed

    Lallemand-Breitenbach, Valérie; Zhu, Jun; Kogan, Scott; Chen, Zhu; de Thé, Hugues

    2005-10-01

    One of the challenges of studying anticancer therapies is that effects observed in cell lines or mouse models are not always good indicators of clinical trial results. The mouse model of acute promyelocytic leukaemia has bucked this trend, as targeted therapies such as retinoic acid and arsenic induce differentiation and clearance of leukaemia cells in both mice and humans. This mouse model has also provided important mechanistic insights into the combinatorial effects of these agents and has promoted combined therapies that have shown recent success in the clinic.

  11. Brain and Plasma Molecular Characterization of the Pathogenic TBI-AD Interrelationship in Mouse Models

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0253 TITLE: Brain and Plasma Molecular Characterization of the Pathogenic TBI-AD Interrelationship in Mouse Models ... brain and plasma responses in mouse models of TBI, AD and other neurodegenerative conditions (Abdullah et al., 2014; Abdullah et al., 2013; Crawford...identify age/time-dependent expression of brain proteins and lipids in mouse models of AD (PSAPP and hTau) and of mTBI (single and repetitive mTBI in hTau

  12. Developing Novel Automated Apparatus for Studying Battery of Social Behaviors in Mutant Mouse Models for Autism

    DTIC Science & Technology

    2013-06-01

    the females). Task 2b: Automated behavioral phenotyping of a mouse model for autism using the video - and RFID-based tracking technology Over the...behavioral traits and the relationship between environmental-gene interactions in mouse models for autism . Finally, since our experimental platform poses no...animal research models . 5 Body Task 1: Develop a combined video - and RFID-based experimental system to allow high- throughput standardized

  13. Behavioral Analysis and Rescue of a Novel Cerebellar Mouse Model of Tuberous Sclerosis Complex

    DTIC Science & Technology

    2012-05-01

    is the three chambered apparatus which has detected social deficits in multiple many mouse models of autism (Kwon et al., 2006; Moy et al., 2004...provides a novel mouse model of TSC-associated autism that would allow for the exploration of cerebellocortical projections and their ability to... autism spectrum disorders. Gene. 496, 88-96. Martin, L. A., et al., Repetitive behavior and increased activity in mice with Purkinje cell loss: a model

  14. Lessons learned from mice and man: mimicking human allergy through mouse models.

    PubMed

    Graham, Michelle T; Nadeau, Kari C

    2014-11-01

    The relevance of using mouse models to represent human allergic pathologies is still unclear. Recent studies suggest the limitations of using models as a standard for assessing immune response and tolerance mechanisms, as mouse models often do not sufficiently depict human atopic conditions. Allergy is a combination of aberrant responses to innocuous environmental agents and the subsequent TH2-mediated inflammatory responses. In this review, we will discuss current paradigms of allergy - specifically, TH2-mediated and IgE-associated immune responses - and current mouse models used to recreate these TH2-mediated pathologies. Our overall goal is to highlight discrepancies that exist between mice and men by examining the advantages and disadvantages of allergic mouse models with respect to the human allergic condition.

  15. Polygenic expression of teratozoospermia and normal fertility in B10.MOL-TEN1 mouse strain.

    PubMed

    Hirawatari, Keitaro; Hanzawa, Naoto; Kuwahara, Maki; Aoyama, Hiroaki; Miura, Ikuo; Wakana, Shigeharu; Gotoh, Hideo

    2015-05-01

    Subfertility and infertility are two major reproductive health problems in human and domestic animals. The contribution of the genotype to these conditions is poorly understood. To examine the genetic basis of male subfertility, we analyzed its relationship to sperm morphology in B10.MOL-TEN1 mice, which shows high-frequencies (about 50%) of morphologically abnormal sperm. Drastic histological changes were also found in the testis of the B10.MOL-TEN1. Segregation analysis showed that the abnormal sperm phenotype in B10.MOL-TEN1 was inherited and was predictably controlled by at least three loci. We also found that male fertility of this strain was normal. These findings indicate a complicated relationship between sperm morphology and male subfertility.

  16. Mouse Model for the Preclinical Study of Metastatic Disease | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Laboratory of Cancer Biology and Genetics, National Cancer Institute seeks partners for collaborative research to co-develop a mouse model that shows preclinical therapeutic response of residual metastatic disease.

  17. HFE gene knockout produces mouse model of hereditary hemochromatosis

    PubMed Central

    Zhou, Xiao Yan; Tomatsu, Shunji; Fleming, Robert E.; Parkkila, Seppo; Waheed, Abdul; Jiang, Jinxing; Fei, Ying; Brunt, Elizabeth M.; Ruddy, David A.; Prass, Cynthia E.; Schatzman, Randall C.; O’Neill, Rosemary; Britton, Robert S.; Bacon, Bruce R.; Sly, William S.

    1998-01-01

    Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload. PMID:9482913

  18. A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN

    DTIC Science & Technology

    2014-09-01

    AWARD NUMBER: W81XWH-13-1-0220 TITLE: A Genetically Engineered Mouse Model of Neuroblastoma ...CONTRACT NUMBER A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN 5b. GRANT NUMBER W81XWH-13-1-0220 5c...common ALK mutations in neuroblastoma , F1174L and R1275Q. We have determined that in tumors cells expressing mutated ALK, different downstream

  19. A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN

    DTIC Science & Technology

    2015-09-01

    AWARD NUMBER: W81XWH-13-1-0220 TITLE: A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN PRINCIPAL...4. TITLE AND SUBTITLE A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN 5a. CONTRACT NUMBER 5b. GRANT NUMBER... genetic and epigenetic changes that occur during tumorigenesis. 15. SUBJECT TERMS Anaplastic lymphoma kinase, neuroblastoma, ALK, ALKF1174L, MYCN, CDK7

  20. Experimental mouse tumour models: what can be learnt about human cancer immunology?

    PubMed

    Dranoff, Glenn

    2011-12-02

    The recent demonstration that cancer immunotherapy extends patient survival has reinvigorated interest in elucidating the role of immunity in tumour pathogenesis. Experimental mouse tumour models have provided key mechanistic insights into host antitumour immune responses, and these have guided the development of novel treatment strategies. To accelerate the translation of these findings into clinical benefits, investigators need to gain a better understanding of the strengths and limitations of mouse model systems as tools for deciphering human antitumour immune responses.

  1. Exploration of a Polygenic Risk Score for Alcohol Consumption: A Longitudinal Analysis from the ALSPAC Cohort

    PubMed Central

    Simpkin, Andrew J.; Haycock, Philip C.; Dudbridge, Frank; Zuccolo, Luisa

    2016-01-01

    Background Uncertainty remains about the true extent by which alcohol consumption causes a number of health outcomes. Genetic variants, or combinations of variants built into a polygenic risk score (PGRS), can be used in an instrumental variable framework to assess causality between a phenotype and disease outcome of interest, a method known as Mendelian randomisation (MR). We aimed to identify genetic variants involved in the aetiology of alcohol consumption, and develop a PGRS for alcohol. Methods Repeated measures of alcohol consumption from mothers and their offspring were collected as part of the Avon Longitudinal Study of Parents and Children. We tested the association between 89 SNPs (identified from either published GWAS data or from functional literature) and repeated measures of alcohol consumption, separately in mothers (from ages 28–48) and offspring (from ages 15–21) who had ever reported drinking. We modelled log units of alcohol using a linear mixed model and calculated beta coefficients for each SNP separately. Cross-validation was used to determine an allelic score for alcohol consumption, and the AVENGEME algorithm employed to estimate variance of the trait explained. Results Following correction for multiple testing, one SNP (rs1229984) showed evidence for association with alcohol consumption (β = -0.177, SE = 0.042, p = <0.0001) in the mothers. No SNPs showed evidence for association in the offspring after correcting for multiple testing. The optimal allelic score was generated using p-value cut offs of 0.5 and 0.05 for the mothers and offspring respectively. These scores explained 0.3% and 0.7% of the variance. Conclusion Our PGRS explains a modest amount of the variance in alcohol consumption and larger sample sizes would be required to use our PGRS in an MR framework. PMID:27902751

  2. Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

    PubMed Central

    Leu, Costin; Balestrini, Simona; Maher, Bridget; Hernández-Hernández, Laura; Gormley, Padhraig; Hämäläinen, Eija; Heggeli, Kristin; Schoeler, Natasha; Novy, Jan; Willis, Joseph; Plagnol, Vincent; Ellis, Rachael; Reavey, Eleanor; O'Regan, Mary; Pickrell, William O.; Thomas, Rhys H.; Chung, Seo-Kyung; Delanty, Norman; McMahon, Jacinta M.; Malone, Stephen; Sadleir, Lynette G.; Berkovic, Samuel F.; Nashef, Lina; Zuberi, Sameer M.; Rees, Mark I.; Cavalleri, Gianpiero L.; Sander, Josemir W.; Hughes, Elaine; Helen Cross, J.; Scheffer, Ingrid E.; Palotie, Aarno; Sisodiya, Sanjay M.

    2015-01-01

    Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10− 3) and non-epilepsy disease controls (P = 1.2 × 10− 3). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP. PMID:26501104

  3. Neuronal mechanism of epileptogenesis in EL mouse.

    PubMed

    Suzuki, Jiro

    2013-01-01

    The convulsions of the EL mouse (EL) were described by Imaizumi et al. in 1954 and were established as epilepsy by Suzuki in 1976. The EL mouse has been kept as an inbred strain and is considered one of the best animal models originated in Japan. The mode of inheritance is autosomal dominant, and environmental risk factors for seizure occurrence are hypothesised to contribute to the polygenic background. Paroxysmal activities in the EL brain arise from the parietal cortex (PCX) and are augmented in the hippocampus, demonstrated by electrophysiology and autoradiography using 2-deoxy glucose when clinical symptoms of seizures appeared. The neurons in the EL PCX, where GABA activity is lower than that of DDY PCX demonstrate increased excitability to proprioceptive sensory input. After repetitive seizure-provoking stimuli, seizures are more easily induced, eventually occurring spontaneously. This phenomenon of "abnormal plasticity" is also observed in the EEG, decreasing GABA activity, expression of the immediately early gene, and various biochemical and molecular processes. This phenomenon is similar to the learning or progressive process of certain neurological diseases.

  4. Intravenous transplantation of mouse embryonic stem cells attenuates demyelination in an ICR outbred mouse model of demyelinating diseases

    PubMed Central

    Pringproa, Kidsadagon; Sathanawongs, Anucha; Khamphilai, Chananthida; Sukkarinprom, Sarocha; Oranratnachai, Apichart

    2016-01-01

    Induction of demyelination in the central nervous system (CNS) of experimental mice using cuprizone is widely used as an animal model for studying the pathogenesis and treatment of demyelination. However, different mouse strains used result in different pathological outcomes. Moreover, because current medicinal treatments are not always effective in multiple sclerosis patients, so the study of exogenous cell transplantation in an animal model is of great importance. The aims of the present study were to establish an alternative ICR outbred mouse model for studying demyelination and to evaluate the effects of intravenous cell transplantation in the present developed mouse model. Two sets of experiments were conducted. Firstly, ICR outbred and BALB/c inbred mice were fed with 0.2% cuprizone for 6 consecutive weeks; then demyelinating scores determined by luxol fast blue stain or immunolabeling with CNPase were evaluated. Secondly, attenuation of demyelination in ICR mice by intravenous injection of mES cells was studied. Scores for demyelination in the brains of ICR mice receiving cell injection (mES cells-injected group) and vehicle (sham-inoculated group) were assessed and compared. The results showed that cuprizone significantly induced demyelination in the cerebral cortex and corpus callosum of both ICR and BALB/c mice. Additionally, intravenous transplantation of mES cells potentially attenuated demyelination in ICR mice compared with sham-inoculated groups. The present study is among the earliest reports to describe the cuprizone-induced demyelination in ICR outbred mice. Although it remains unclear whether mES cells or trophic effects from mES cells are the cause of enhanced remyelination, the results of the present study may shed some light on exogenous cell therapy in central nervous system demyelinating diseases. PMID:27904491

  5. Optical coherence tomography for live phenotypic analysis of embryonic ocular structures in mouse models

    NASA Astrophysics Data System (ADS)

    Larina, Irina V.; Syed, Saba H.; Sudheendran, Narendran; Overbeek, Paul A.; Dickinson, Mary E.; Larin, Kirill V.

    2012-08-01

    Mouse models of ocular diseases provide a powerful resource for exploration of molecular regulation of eye development and pre-clinical studies. Availability of a live high-resolution imaging method for mouse embryonic eyes would significantly enhance longitudinal analyses and high-throughput morphological screening. We demonstrate that optical coherence tomography (OCT) can be used for live embryonic ocular imaging throughout gestation. At all studied stages, the whole eye is within the imaging distance of the system and there is a good optical contrast between the structures. We also performed OCT eye imaging in the embryonic retinoblastoma mouse model Pax6-SV40 T-antigen, which spontaneously forms lens and retinal lesions, and demonstrate that OCT allows us to clearly differentiate between the mutant and wild type phenotypes. These results demonstrate that OCTin utero imaging is a potentially useful tool to study embryonic ocular diseases in mouse models.

  6. Cross Species Genomic Analysis Identifies a Mouse Model as Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma

    PubMed Central

    Mito, Jeffrey K.; Riedel, Richard F.; Dodd, Leslie; Lahat, Guy; Lazar, Alexander J.; Dodd, Rebecca D.; Stangenberg, Lars; Eward, William C.; Hornicek, Francis J.; Yoon, Sam S.; Brigman, Brian E.; Jacks, Tyler; Lev, Dina; Mukherjee, Sayan; Kirsch, David G.

    2009-01-01

    Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-KrasG12D; Trp53Flox/Flox mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model. PMID:19956606

  7. Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease.

    PubMed

    Tosini, Gianluca; Owino, Sharon; Guillaume, Jean-Luc; Jockers, Ralf

    2014-08-01

    Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2 , which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1 /MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models.

  8. A Mouse Model for Binge-Level Methamphetamine Use

    PubMed Central

    Shabani, Shkelzen; Houlton, Sydney K.; Hellmuth, Laura; Mojica, Erika; Mootz, John R. K.; Zhu, Zhen; Reed, Cheryl; Phillips, Tamara J.

    2016-01-01

    Binge/crash cycles of methamphetamine (MA) use are frequently reported by individuals suffering from MA use disorders. A MA binge is self-reported as multiple daily doses that commonly accumulate to 800 mg/day (~10 mg/kg/day for a 170 pound human). A genetic animal model with a similar vulnerability to binge-level MA intake is missing. We used selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mouse lines to determine whether several procedural variations would result in binge-level MA intake. Data were also collected in two progenitor populations of the MA drinking lines, the DBA/2J (D2) strain and the F2 cross of the D2 and C57BL/6J strains. The impact of 3 factors was examined: (1) concentration of MA in the two-bottle choice procedure used for selective breeding; (2) ratio of bottles containing MA vs. water, and (3) length of the withdrawal (or abstinence) period between MA drinking sessions. When MA concentration was progressively increased every 4 days in 20 mg/l amounts from 20 to 140 mg/l, maximum intake in MALDR mice was 1.1 mg/kg, whereas MAHDR mice consumed as much as 14.6 mg/kg. When these concentrations were tested in a multiple bottle choice procedure, the highest ratio of MA to water bottles (3:1) was associated with escalated MA intake of up to 29.1 mg/kg in MAHDR mice and 12.0 mg/kg in F2 mice; MALDR mice did not show a ratio-dependent escalation in MA intake. Finally, MAHDR and D2 mice were offered 3 bottles of MA vs. water at increasing concentrations from 20 to 80 mg/l, and tested under an intermittent 6-h withdrawal period, which was lengthened to 30 h (D2 mice) or to 30 or 78 h (MAHDR). D2 and MAHDR mice initially consumed similar amounts of 14–16 mg/kg MA, but D2 mice reduced their MA intake 3-fold after introduction of 30-h abstinence periods, whereas MAHDR mice retained their high level of intake regardless of withdrawal period. MAHDR mice provide a genetic model of binge-level MA intake appropriate for the study of

  9. Diabetic wound healing in a MMP9-/- mouse model.

    PubMed

    Cho, Hongkwan; Balaji, Swathi; Hone, Natalie L; Moles, Chad M; Sheikh, Abdul Q; Crombleholme, Timothy M; Keswani, Sundeep G; Narmoneva, Daria A

    2016-09-01

    Reduced mobilization of endothelial progenitor cells (EPCs) from the bone marrow (BM) and impaired EPC recruitment into the wound represent a fundamental deficiency in the chronic ulcers. However, mechanistic understanding of the role of BM-derived EPCs in cutaneous wound neovascularization and healing remains incomplete, which impedes development of EPC-based wound healing therapies. The objective of this study was to determine the role of EPCs in wound neovascularization and healing both under normal conditions and using single deficiency (EPC) or double-deficiency (EPC + diabetes) models of wound healing. MMP9 knockout (MMP9 KO) mouse model was utilized, where impaired EPC mobilization can be rescued by stem cell factor (SCF). The hypotheses were: (1) MMP9 KO mice exhibit impaired wound neovascularization and healing, which are further exacerbated with diabetes; (2) these impairments can be rescued by SCF administration. Full-thickness excisional wounds with silicone splints to minimize contraction were created on MMP9 KO mice with/without streptozotocin-induced diabetes in the presence or absence of tail-vein injected SCF. Wound morphology, vascularization, inflammation, and EPC mobilization and recruitment were quantified at day 7 postwounding. Results demonstrate no difference in wound closure and granulation tissue area between any groups. MMP9 deficiency significantly impairs wound neovascularization, increases inflammation, decreases collagen deposition, and decreases peripheral blood EPC (pb-EPC) counts when compared with wild-type (WT). Diabetes further increases inflammation, but does not cause further impairment in vascularization, as compared with MMP9 KO group. SCF improves neovascularization and increases EPCs to WT levels (both nondiabetic and diabetic MMP9 KO groups), while exacerbating inflammation in all groups. SCF rescues EPC-deficiency and impaired wound neovascularization in both diabetic and nondiabetic MMP9 KO mice. Overall, the

  10. A Mouse Model for Binge-Level Methamphetamine Use.

    PubMed

    Shabani, Shkelzen; Houlton, Sydney K; Hellmuth, Laura; Mojica, Erika; Mootz, John R K; Zhu, Zhen; Reed, Cheryl; Phillips, Tamara J

    2016-01-01

    Binge/crash cycles of methamphetamine (MA) use are frequently reported by individuals suffering from MA use disorders. A MA binge is self-reported as multiple daily doses that commonly accumulate to 800 mg/day (~10 mg/kg/day for a 170 pound human). A genetic animal model with a similar vulnerability to binge-level MA intake is missing. We used selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mouse lines to determine whether several procedural variations would result in binge-level MA intake. Data were also collected in two progenitor populations of the MA drinking lines, the DBA/2J (D2) strain and the F2 cross of the D2 and C57BL/6J strains. The impact of 3 factors was examined: (1) concentration of MA in the two-bottle choice procedure used for selective breeding; (2) ratio of bottles containing MA vs. water, and (3) length of the withdrawal (or abstinence) period between MA drinking sessions. When MA concentration was progressively increased every 4 days in 20 mg/l amounts from 20 to 140 mg/l, maximum intake in MALDR mice was 1.1 mg/kg, whereas MAHDR mice consumed as much as 14.6 mg/kg. When these concentrations were tested in a multiple bottle choice procedure, the highest ratio of MA to water bottles (3:1) was associated with escalated MA intake of up to 29.1 mg/kg in MAHDR mice and 12.0 mg/kg in F2 mice; MALDR mice did not show a ratio-dependent escalation in MA intake. Finally, MAHDR and D2 mice were offered 3 bottles of MA vs. water at increasing concentrations from 20 to 80 mg/l, and tested under an intermittent 6-h withdrawal period, which was lengthened to 30 h (D2 mice) or to 30 or 78 h (MAHDR). D2 and MAHDR mice initially consumed similar amounts of 14-16 mg/kg MA, but D2 mice reduced their MA intake 3-fold after introduction of 30-h abstinence periods, whereas MAHDR mice retained their high level of intake regardless of withdrawal period. MAHDR mice provide a genetic model of binge-level MA intake appropriate for the study of

  11. Modeling Phenotypes of Tuberous Sclerosis in the Mouse

    DTIC Science & Technology

    2006-02-01

    other proteins in this pathological progression, and to evaluate relevant therapeutic interventions such as rapamycin. 15. SUBJECT TERMS MOUSE...whether rapamycin treatment corrects this dysregulation, and whether phenotypes seen in the mice are abrogated by breeding pertinent MMP knockout...induction by doxycycline (Figure 7), this approach did not yield a phenotype, at least after 6 months of doxycycline treatment . Thus, as our

  12. A novel mouse xenotransplantation model of EBV-T/NK-LPD and the application of the mouse model.

    PubMed

    Imadome, Ken-Ichi

    2013-01-01

    Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by proliferation of EBV-infected T or NK cells, is a disease of unknown pathogenesis and requires hematopoietic stem cell transplantation for curative treatment. Here we show that intravenous injection of peripheral blood mononuclear cells (PBMCs) isolated from patients with CAEBV to NOD/Shi-scid/IL-2R γ(null) (NOG) mice leads to engraftment of EBV-infected T or NK cells. Analysis of TCR repertoire identified an identical predominant EBV-infected T-cell clone both in a patient and a mouse transplanted with his PBMCs. EBV-infected T or NK cells infiltrated to most major organs including the liver, spleen, lungs, kidneys, adrenal glands, and intestine, showing histological characteristics of CAEBV. Expression of EBNA1, LMP1, and LMP2A, but not EBNA2, in these cells indicated the latency II program of EBV gene characteristic to CAEBV. High levels of TNF-α, IFN-γ, and RANTES were detected in the peripheral blood of these mice. EBV-containing fractions of either CD8(+), γδT, or NK cell lineages failed to engraft, once they were isolated from PBMCs ; they could engraft only when CD4(+) cell fraction was transplanted in parallel. Isolated EBV-containing CD4(+) T cells, in contrast, did engraft on their own. This is the first report of an animal model of CAEBV and suggest that EBV-infected T or NK cells in CAEBV are not truly neoplastic but are dependent on CD4(+) T cells for their proliferation in vivo.

  13. Estimating effects of a single gene and polygenes on quantitative traits from a diallel design.

    PubMed

    Lou, Xiang-Yang; Yang, Mark C K

    2006-01-01

    A genetic model is developed with additive and dominance effects of a single gene and polygenes as well as general and specific reciprocal effects for the progeny from a diallel mating design. The methods of ANOVA, minimum norm quadratic unbiased estimation (MINQUE), restricted maximum likelihood estimation (REML), and maximum likelihood estimation (ML) are suggested for estimating variance components, and the methods of generalized least squares (GLS) and ordinary least squares (OLS) for fixed effects, while best linear unbiased prediction, linear unbiased prediction (LUP), and adjusted unbiased prediction are suggested for analyzing random effects. Monte Carlo simulations were conducted to evaluate the unbiasedness and efficiency of statistical methods involving two diallel designs with commonly used sample sizes, 6 and 8 parents, with no and missing crosses, respectively. Simulation results show that GLS and OLS are almost equally efficient for estimation of fixed effects, while MINQUE (1) and REML are better estimators of the variance components and LUP is most practical method for prediction of random effects. Data from a Drosophila melanogaster experiment (Gilbert 1985a, Theor appl Genet 69:625-629) were used as a working example to demonstrate the statistical analysis. The new methodology is also applicable to screening candidate gene(s) and to other mating designs with multiple parents, such as nested (NC Design I) and factorial (NC Design II) designs. Moreover, this methodology can serve as a guide to develop new methods for detecting indiscernible major genes and mapping quantitative trait loci based on mixture distribution theory. The computer program for the methods suggested in this article is freely available from the authors.

  14. Two-Pore Channels: Lessons from Mutant Mouse Models

    PubMed Central

    Ruas, Margarida; Galione, Antony; Parrington, John

    2016-01-01

    Recent interest in two-pore channels (TPCs) has resulted in a variety of studies dealing with the functional role and mechanism of action of these endo-lysosomal proteins in diverse physiological processes. With the availability of mouse lines harbouring mutant alleles for Tpcnl and/or Tpcn2 genes, several studies have made use of them to validate, consolidate and discover new roles for these channels not only at the cellular level but, importantly, also at the level of the whole organism. The different mutant mouse lines that have been used were derived from distinct genetic manipulation strategies, with the aim of knocking out expression of TPC proteins. However, the expression of different residual TPC sequences predicted to occur in these mutant mouse lines, together with the varied degree to which the effects on Tpcn expression have been studied, makes it important to assess the true knockout status of some of the lines. In this review we summarize these Tpcn mutant mouse lines with regard to their predicted effect on Tpcn expression and the extent to which they have been characterized. Additionally, we discuss how results derived from studies using these Tpcn mutant mouse lines have consolidated previously proposed roles for TPCs, such as mediators of NAADP signalling, endo-lysosomal functions, and pancreatic β cell physiology. We will also review how they have been instrumental in the assignment of new physiological roles for these cation channels in processes such as membrane electrical excitability, neoangiogenesis, viral infection and brown adipose tissue and heart function, revealing, in some cases, a specific contribution of a particular TPC isoform. PMID:27330869

  15. [Relevance of animal models in the study of human pathologies: a mouse model of Down syndrome].

    PubMed

    Morice, Elise

    2010-01-01

    Animal models provide a simplified representation of biological systems impossible to study directly in the human being. Regarding genetic pathologies, mouse models are the most studied since they enable to reproduce in animals the mutation of the gene or genes responsible for the disease and to study the phenotypic consequences. Down syndrome is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21) and is characterized by different degrees of phenotypic alterations including morphological, cardiac, muscular, cerebral, motor and intellectual changes. This high phenotypic heterogeneity involves genetic and environmental effects, which are impossible to dissect out in human beings. Various models in mice have been developed in order to identify the genetic and neurobiological mechanisms responsible for Down syndrome. The Tc1 mouse is the most complete genetic animal model currently available to study Down syndrome, since it carries an almost complete Hsa 21. The behavioural and electrophysiological studies of this model reveal a great similarity between the animal phenotype and the Down syndrome symptomatology, consequently this model represents a powerful genetic tool with a potential to unravel the mechanisms underlying the deficiencies array characteristic of this human condition. In the long term, Tc1 mice will contribute to the development and the screening of new therapeutics, with the goal of improving all the impairments reported in Down syndrome.

  16. A Humanized Mouse Model for the Reduced Folate Carrier

    PubMed Central

    Patterson, David; Graham, Christine; Cherian, Christina; Matherly, Larry H.

    2008-01-01

    The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by 5 major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5’ untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776 bp coding sequence. The 5’ non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5’UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5’UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5’UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered

  17. What do mouse models of muscular dystrophy tell us about the DAPC and its components?

    PubMed

    Whitmore, Charlotte; Morgan, Jennifer

    2014-12-01

    There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated.

  18. Identification of Tumor Rejection Antigens for Breast Cancer Using a Mouse Tumor Rejection Model

    DTIC Science & Technology

    2007-05-01

    of the mouse antigens. This comprehensive evaluation will only be performed to the antigens that show tumor protection effect in mice ; 3) test the...from the same mouse . The expression profile of these antigens were examined using real time RT-PCR. RNA was extracted from 3 normal...than tumor bearing mice is more likely to yield therapeutically relevant targets. We recognize that tumor implant model is not optimal in testing

  19. The Role of Skeletal Muscle in External Ear Development: A Mouse Model Histomorphometric Study

    PubMed Central

    Rot, Irena

    2015-01-01

    Background: Mechanical stimuli imparted by skeletal muscles play an important role during embryonic development in vertebrates. Little is known whether skeletal muscles are required for normal external ear development. Methods: We used Myf5−/−:MyoD−/− (double-mutant) mouse embryos that completely lack skeletal musculature and analyzed the development of the external ear. We concentrated on the external ear because several studies have suggested a muscular cause to various congenital auricular deformities, and middle and inner ear development was previously reported using the same mouse model. Wild-type mouse embryos were used as controls to compare the histomorphometric outcomes. Results: Our findings demonstrated an absence of the external auditory meatus, along with an abnormal auricular appearance, in the double-mutant mouse embryos. Specifically, the auricle did not protrude laterally as noted in the wild-type mouse ears. However, histomorphometric measurements were not significantly different between the wild-type and double-mutant mouse ears. Conclusion: Overall, our study showed that the development of the mouse external ear is dependent on the presence of skeletal muscles. PMID:26090272

  20. Development of a mouse model of supraspinatus tendon insertion site healing.

    PubMed

    Bell, Rebecca; Taub, Peter; Cagle, Paul; Flatow, Evan L; Andarawis-Puri, Nelly

    2015-01-01

    Supraspinatus (SS) tendon tears are common musculoskeletal injuries whose surgical repair exhibits the highest incidence of re-tear of any tendon. Development of therapeutics for improving SS tendon healing is impaired by the lack of a model that allows biological perturbations to identify mechanisms that underlie ineffective healing. The objective of this study was to develop a mouse model of supraspinatus insertion site healing by creating a reproducible SS tendon detachment and surgical repair which can be applied to a wide array of inbred mouse strains and genetic mutants. Anatomical and structural analyses confirmed that the rotator cuff of the mouse is similar to that of human, including the presence of a coracoacromial (CA) arch and an insertion site that exhibits a fibrocartilagenous transition zone. The surgical repair was successfully conducted on seven strains of mice that are commonly used in Orthopaedic Research suggesting that the procedure can be applied to most inbred strains and genetic mutants. The quality of the repair was confirmed with histology through 14 days after surgery in two mouse strains that represent the variation in mouse strains evaluated. The developed mouse model will allow us to investigate mechanisms involved in insertion site healing.

  1. Ovarian Mouse Models with Targeted Fallopian Tubal Carcinogenesis

    DTIC Science & Technology

    2012-09-01

    serous subtype of epithelial ovarian cancer may also arise from the fallopian epithelium. This shift in cell-of-origin for ovarian cancer has...hypothesis that high-grade serous ovarian cancer may arise from fallopian tubal epithelium are lacking. Therefore, in this proposal we generated a mouse...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT To test the idea that ovarian cancer arises from oviductal

  2. An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present.

    PubMed

    Jacobs, Ans; Warda, Anne-Sophie; Verbeek, Jef; Cassiman, David; Spincemaille, Pieter

    2016-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc.

  3. Defining the role of polyamines in colon carcinogenesis using mouse models

    PubMed Central

    Ignatenko, Natalia A.; Gerner, Eugene W.; Besselsen, David G.

    2011-01-01

    Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM) models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min) mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention. PMID:21712957

  4. Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds.

    PubMed

    Makhaeva, Galina F; Rudakova, Elena V; Hein, Nichole D; Serebryakova, Olga G; Kovaleva, Nadezhda V; Boltneva, Natalia P; Fink, John K; Richardson, Rudy J

    2014-12-01

    Inhibition and aging of neuropathy target esterase (NTE) by neuropathic organophosphorus (OP) compounds triggers OP compound-induced delayed neuropathy (OPIDN), whereas inhibition of acetylcholinesterase (AChE) produces cholinergic toxicity. The neuropathic potential of an OP compound is defined by its relative inhibitory potency toward NTE vs. AChE assessed by enzyme assays following dosing in vivo or after incubations of direct-acting compounds or active metabolites with enzymes in vitro. The standard animal model of OPIDN is the adult hen, but its large size and high husbandry costs make this species a burdensome model for assessing neuropathic potential. Although the mouse does not readily exhibit clinical signs of OPIDN, it displays axonal lesions and expresses brain AChE and NTE. Therefore, the present research was performed as a further test of the hypothesis that inhibition of mouse brain AChE and NTE could be used to assess neuropathic potential using mouse brain preparations in vitro or employing mouse brain assays following dosing of OP compounds in vivo. Excellent correlations were obtained for inhibition kinetics in vitro of mouse brain enzymes vs. hen brain and human recombinant enzymes. Furthermore, inhibition of mouse brain AChE and NTE after dosing with OP compounds afforded ED(50) ratios that agreed with relative inhibitory potencies assessed in vitro. Taken together, results with mouse brain enzymes demonstrated consistent correspondence between in vitro and in vivo predictors of neuropathic potential, thus adding to previous studies supporting the validity of a mouse model for biochemical assessment of the ability of OP compounds to produce OPIDN.

  5. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders

    PubMed Central

    Scattoni, Maria Luisa; Crawley, Jacqueline; Ricceri, Laura

    2009-01-01

    In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behavior of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. All these vocalizations are becoming an increasingly valuable assay for behavioral phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) – originally identified and investigated in rats - can be measured in C57Bl/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioral phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. PMID:18771687

  6. Ultrastructural study of Rift Valley fever virus in the mouse model

    SciTech Connect

    Reed, Christopher; Steele, Keith E.; Honko, Anna; Shamblin, Joshua; Hensley, Lisa E.; Smith, Darci R.

    2012-09-15

    Detailed ultrastructural studies of Rift Valley fever virus (RVFV) in the mouse model are needed to develop and characterize a small animal model of RVF for the evaluation of potential vaccines and therapeutics. In this study, the ultrastructural features of RVFV infection in the mouse model were analyzed. The main changes in the liver included the presence of viral particles in hepatocytes and hepatic stem cells accompanied by hepatocyte apoptosis. However, viral particles were observed rarely in the liver; in contrast, particles were extremely abundant in the CNS. Despite extensive lymphocytolysis, direct evidence of viral replication was not observed in the lymphoid tissue. These results correlate with the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF, but suggest that host immune-mediated mechanisms contribute significantly to pathology. The results of this study expand our knowledge of RVFV-host interactions and further characterize the mouse model of RVF.

  7. New statistical approaches exploit the polygenic architecture of schizophrenia - implications for the underlying neurobiology

    PubMed Central

    Schork, Andrew J.; Wang, Yunpeng; Thompson, Wesley K.; Dale, Anders M.; Andreassen, Ole A.

    2017-01-01

    Schizophrenia is a complex disorder with high heritability. Recent findings from several large genetic studies suggest a large number of risk variants are involved (i.e., schizophrenia is a polygenic disorder) and analytic approaches could be tailored for this scenario. Novel statistical approaches for analyzing GWAS data have recently been developed to be more sensitive to polygenic traits. These approaches have provided intriguing new insights into neurobiological pathways and support for the involvement of regulatory mechanisms, neurotransmission (glutamate, dopamine, GABA), and immune and neurodevelopmental pathways. Integrating the emerging statistical genetics evidence with sound neurobiological experiments will be a critical, and challenging, next step in deciphering the specific disease mechanisms of schizophrenia. PMID:26555806

  8. Response of Polygenic Traits Under Stabilizing Selection and Mutation When Loci Have Unequal Effects

    PubMed Central

    Jain, Kavita; Stephan, Wolfgang

    2015-01-01

    We consider an infinitely large population under stabilizing selection and mutation in which the allelic effects determining a polygenic trait vary between loci. We obtain analytical expressions for the stationary genetic variance as a function of the distribution of effects, mutation rate, and selection coefficient. We also study the dynamics of the allele frequencies, focusing on short-term evolution of the phenotypic mean as it approaches the optimum after an environmental change. We find that when most effects are small, the genetic variance does not change appreciably during adaptation, and the time until the phenotypic mean reaches the optimum is short if the number of loci is large. However, when most effects are large, the change of the variance during the adaptive process cannot be neglected. In this case, the short-term dynamics may be described by those of a few loci of large effect. Our results may be used to understand polygenic selection driving rapid adaptation. PMID:25834214

  9. Are mouse models of human mycobacterial diseases relevant? Genetics says: ‘yes!’

    PubMed Central

    Apt, Alexander S

    2011-01-01

    Relevance and accuracy of experimental mouse models of tuberculosis (TB) are the subject of constant debate. This article briefly reviews genetic aspects of this problem and provides a few examples of mycobacterial diseases with similar or identical genetic control in mice and humans. The two species display more similarities than differences regarding both genetics of susceptibility/severity of mycobacterial diseases and the networks of protective and pathological immune reactions. In the opinion of the author, refined mouse models of mycobacterial diseases are extremely useful for modelling the corresponding human conditions, if genetic diversity is taken into account. PMID:21896006

  10. SNP-based heritability estimates of the personality dimensions and polygenic prediction of both neuroticism and major depression: findings from CONVERGE.

    PubMed

    Docherty, A R; Moscati, A; Peterson, R; Edwards, A C; Adkins, D E; Bacanu, S A; Bigdeli, T B; Webb, B T; Flint, J; Kendler, K S

    2016-10-25

    Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case-control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 × 10(-6)). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism

  11. SNP-based heritability estimates of the personality dimensions and polygenic prediction of both neuroticism and major depression: findings from CONVERGE

    PubMed Central

    Docherty, A R; Moscati, A; Peterson, R; Edwards, A C; Adkins, D E; Bacanu, S A; Bigdeli, T B; Webb, B T; Flint, J; Kendler, K S

    2016-01-01

    Biometrical genetic studies suggest that the personality dimensions, including neuroticism, are moderately heritable (~0.4 to 0.6). Quantitative analyses that aggregate the effects of many common variants have recently further informed genetic research on European samples. However, there has been limited research to date on non-European populations. This study examined the personality dimensions in a large sample of Han Chinese descent (N=10 064) from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology study, aimed at identifying genetic risk factors for recurrent major depression among a rigorously ascertained cohort. Heritability of neuroticism as measured by the Eysenck Personality Questionnaire (EPQ) was estimated to be low but statistically significant at 10% (s.e.=0.03, P=0.0001). In addition to EPQ, neuroticism based on a three-factor model, data for the Big Five (BF) personality dimensions (neuroticism, openness, conscientiousness, extraversion and agreeableness) measured by the Big Five Inventory were available for controls (n=5596). Heritability estimates of the BF were not statistically significant despite high power (>0.85) to detect heritabilities of 0.10. Polygenic risk scores constructed by best linear unbiased prediction weights applied to split-half samples failed to significantly predict any of the personality traits, but polygenic risk for neuroticism, calculated with LDpred and based on predictive variants previously identified from European populations (N=171 911), significantly predicted major depressive disorder case–control status (P=0.0004) after false discovery rate correction. The scores also significantly predicted EPQ neuroticism (P=6.3 × 10−6). Factor analytic results of the measures indicated that any differences in heritabilities across samples may be due to genetic variation or variation in haplotype structure between samples, rather than measurement non-invariance. Findings demonstrate that neuroticism

  12. Are mouse models of asthma appropriate for investigating the pathogenesis of airway hyper-responsiveness?

    PubMed Central

    Kumar, Rakesh K.; Foster, Paul S.

    2012-01-01

    Whether mouse models of chronic asthma can be used to investigate the relationship between airway inflammation/remodeling and airway hyper-responsiveness (AHR) is a vexed question. It raises issues about the extent to which such models replicate key features of the human disease. Here, we review some of the characteristic pathological features of human asthma and their relationship to AHR and examine some limitations of mouse models that are commonly used to investigate these relationships. We compare these conventional models with our mouse model of chronic asthma involving long-term low-level inhalational challenge and review studies of the relationship between inflammation/remodeling and AHR in this model and its derivatives, including models of an acute exacerbation of chronic asthma and of the induction phase of childhood asthma. We conclude that while extrapolating from studies in mouse models to AHR in humans requires cautious interpretation, such experimental work can provide significant insights into the pathogenesis of airway responsiveness and its molecular and cellular regulation. PMID:23060800

  13. A transgenic mouse model of hemoglobin S Antilles disease.

    PubMed

    Popp, R A; Popp, D M; Shinpock, S G; Yang, M Y; Mural, J G; Aguinaga, M P; Kopsombut, P; Roa, P D; Turner, E A; Rubin, E M

    1997-06-01

    Hemoglobin (Hb) S Antilles is a naturally occurring form of sickling human Hb but causes a more severe phenotype than Hb S. Two homozygous viable Hb S Antilles transgene insertions from Tg58Ru and Tg98Ru mice were bred into MHOAH mice that express high oxygen affinity (P50 approximately 24.5 mm Hg) rather than normal (P50 approximately 40 mm Hg) mouse Hbs. The rationale was that the high oxygen affinity MHOAH Hb, the lower oxygen affinity of Hb S Antilles than Hb S (P50 approximately 40 v 26.5 mm Hg), and the lower solubility of deoxygenated Hb S Antilles than Hb S (approximately 11 v 18 g/dL) would favor deoxygenation and polymerization of human Hb S Antilles in MHOAH mouse red blood cells (RBCs). The Tg58 x Tg98 mice produced have a high and balanced expression (approximately 50% each) of h alpha and h beta(S Antilles) globins, 25% to 35% of their RBCs are misshapen in vivo, and in vitro deoxygenation of their blood induces 30% to 50% of the RBCs to form classical looking, elongated sickle cells with pointed ends. Tg58 x Tg98 mice exhibit reticulocytosis, an elevated white blood cell count and lung and kidney pathology commonly found in sickle cell patients, which should make these mice useful for experimental studies on possible therapeutic intervention of sickle cell disease.

  14. Neuronal mechanisms and circuits underlying repetitive behaviors in mouse models of autism spectrum disorder.

    PubMed

    Kim, Hyopil; Lim, Chae-Seok; Kaang, Bong-Kiun

    2016-01-20

    Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by three central behavioral symptoms: impaired social interaction, impaired social communication, and restricted and repetitive behaviors. However, the symptoms are heterogeneous among patients and a number of ASD mouse models have been generated containing mutations that mimic the mutations found in human patients with ASD. Each mouse model was found to display a unique set of repetitive behaviors. In this review, we summarize the repetitive behaviors of the ASD mouse models and variations found in their neural mechanisms including molecular and electrophysiological features. We also propose potential neuronal mechanisms underlying these repetitive behaviors, focusing on the role of the cortico-basal ganglia-thalamic circuits and brain regions associated with both social and repetitive behaviors. Further understanding of molecular and circuitry mechanisms of the repetitive behaviors associated with ASD is necessary to aid the development of effective treatments for these disorders.

  15. Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism.

    PubMed

    Wang, Miao; Li, Huiping; Takumi, Toru; Qiu, Zilong; Xu, Xiu; Yu, Xiang; Bian, Wen-Jie

    2017-04-01

    Autism spectrum disorder (ASD) encompasses a complex set of developmental neurological disorders, characterized by deficits in social communication and excessive repetitive behaviors. In recent years, ASD is increasingly being considered as a disease of the synapse. One main type of genetic aberration leading to ASD is gene duplication, and several mouse models have been generated mimicking these mutations. Here, we studied the effects of MECP2 duplication and human chromosome 15q11-13 duplication on synaptic development and neural circuit wiring in the mouse sensory cortices. We showed that mice carrying MECP2 duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation. Our results demonstrate that spine pathology varies significantly between autism models and that distinct aspects of neural circuit development may be targeted in different ASD mutations. Our results further underscore the importance of gene dosage in normal development and function of the brain.

  16. Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome.

    PubMed

    de Souza, Fabio M Simoes; Busquet, Nicolas; Blatner, Megan; Maclean, Kenneth N; Restrepo, Diego

    2011-01-01

    Down syndrome (DS) is the most common form of congenital intellectual disability. Although DS involves multiple disturbances in various tissues, there is little doubt that in terms of quality of life cognitive impairment is the most serious facet and there is no effective treatment for this aspect of the syndrome. The Ts65Dn mouse model of DS recapitulates multiple aspects of DS including cognitive impairment. Here the Ts65Dn mouse model of DS was evaluated in an associative learning paradigm based on olfactory cues. In contrast to disomic controls, trisomic mice exhibited significant deficits in olfactory learning. Treatment of trisomic mice with the acetylcholinesterase inhibitor galantamine resulted in a significant improvement in olfactory learning. Collectively, our study indicates that olfactory learning can be a sensitive tool for evaluating deficits in associative learning in mouse models of DS and that galantamine has therapeutic potential for improving cognitive abilities.

  17. Integrating model behavior, optimization, and sensitivity/uncertainty analysis: overview and application of the MOUSE software toolbox

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This paper provides an overview of the Model Optimization, Uncertainty, and SEnsitivity Analysis (MOUSE) software application, an open-source, Java-based toolbox of visual and numerical analysis components for the evaluation of environmental models. MOUSE is based on the OPTAS model calibration syst...

  18. Characterizing the Relationship Between Blast Exposure and Mild TBI with Dynamic Modeling and Testing in a New Mouse Model

    DTIC Science & Technology

    2010-07-31

    laboratory-based animal experiments are being conducted to determine the impact forces that induce single or repetitive mTBI in mice . A 0.196J impact to the...TITLE: Characterizing the relationship between blast exposure and mild TBI with dynamic modeling and testing in a new mouse model PRINCIPAL...exposure and 5a. CONTRACT NUMBER Mild TBI with dynamic modeling and testing in a new mouse model 5b. GRANT NUMBER W81XWH-08-1-0289 5c. PROGRAM

  19. Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy.

    PubMed

    Rooney, Jachinta E; Gurpur, Praveen B; Burkin, Dean J

    2009-05-12

    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The alpha(7)beta(1)-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the alpha(7)-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate alpha(7)-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for alpha(7)-integrin expression. We show that laminin-111 (alpha(1), beta(1), gamma(1)), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased alpha(7)-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha(7)-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

  20. Model-Based Tumor Growth Dynamics and Therapy Response in a Mouse Model of De Novo Carcinogenesis

    PubMed Central

    Hadjiandreou, Marios M.; Rizki, Gizem; Achilleos, Achilleas; Strati, Katerina; Mitsis, Georgios D.

    2015-01-01

    Tumorigenesis is a complex, multistep process that depends on numerous alterations within the cell and contribution from the surrounding stroma. The ability to model macroscopic tumor evolution with high fidelity may contribute to better predictive tools for designing tumor therapy in the clinic. However, attempts to model tumor growth have mainly been developed and validated using data from xenograft mouse models, which fail to capture important aspects of tumorigenesis including tumor-initiating events and interactions with the immune system. In the present study, we investigate tumor growth and therapy dynamics in a mouse model of de novo carcinogenesis that closely recapitulates tumor initiation, progression and maintenance in vivo. We show that the rate of tumor growth and the effects of therapy are highly variable and mouse specific using a Gompertz model to describe tumor growth and a two-compartment pharmacokinetic/ pharmacodynamic model to describe the effects of therapy in mice treated with 5-FU. We show that inter-mouse growth variability is considerably larger than intra-mouse variability and that there is a correlation between tumor growth and drug kill rates. Our results show that in vivo tumor growth and regression in a double transgenic mouse model are highly variable both within and between subjects and that mathematical models can be used to capture the overall characteristics of this variability. In order for these models to become useful tools in the design of optimal therapy strategies and ultimately in clinical practice, a subject-specific modelling strategy is necessary, rather than approaches that are based on the average behavior of a given subject population which could provide erroneous results. PMID:26649886

  1. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

    PubMed Central

    Pérès, Eléonore; Bagdassarian, Eugénie; This, Sébastien; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

    2015-01-01

    The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed. PMID:26690200

  2. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis.

    PubMed

    Pérès, Eléonore; Bagdassarian, Eugénie; This, Sébastien; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

    2015-12-07

    The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.

  3. [Utilization of Werner syndrome mouse model in studying premature aging and tumor].

    PubMed

    Jia, Shu-Ting; Yang, Shi-Hua; Luo, Ying

    2009-08-01

    Werner syndrome (WS) is a rare autosomal recessive genetic disease in human. It is considered as a good model disease in studying human premature syndrome. Werner protein (WRN) is a nuclear protein mutated in WS. Recent biochemical and genetic studies indicated that WRN plays important roles in DNA replication, DNA repair, and telomere maintenance. Here, we reviewed the molecular genetics of WS and the importance of telomere and WRN in the development of WS. Knocking out both telomerase and Wrn genes in mouse faithfully manifests human WS. The mouse model provides a unique genetic platform to explore the crosstalk of premature aging and tumor.

  4. Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure.

    PubMed

    Sheng, Jonathan; Wang, Yi; Turesky, Robert J; Kluetzman, Kerri; Zhang, Qing-Yu; Ding, Xinxin

    2016-05-16

    Albumin is a commonly used serum protein for studying human exposure to xenobiotic compounds, including therapeutics and environmental pollutants. Often, the reactivity of albumin with xenobiotic compounds is studied ex vivo with human albumin or plasma/serum samples. Some studies have characterized the reactivity of albumin with chemicals in rodent models; however, differences between the orthologous peptide sequences of human and rodent albumins can result in the formation of different types of chemical-protein adducts with different interaction sites or peptide sequences. Our goal is to generate a human albumin transgenic mouse model that can be used to establish human protein biomarkers of exposure to hazardous xenobiotics for human risk assessment via animal studies. We have developed a human albumin transgenic mouse model and characterized the genotype and phenotype of the transgenic mice. The presence of the human albumin gene in the genome of the model mouse was confirmed by genomic PCR analysis, whereas liver-specific expression of the transgenic human albumin mRNA was validated by RT-PCR analysis. Further immunoblot and mass spectrometry analyses indicated that the transgenic human albumin protein is a full-length, mature protein, which is less abundant than the endogenous mouse albumin that coexists in the serum of the transgenic mouse. The transgenic protein was able to form ex vivo adducts with a genotoxic metabolite of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a procarcinogenic heterocyclic aromatic amine formed in cooked meat. This novel human albumin transgenic mouse model will facilitate the development and validation of albumin-carcinogen adducts as biomarkers of xenobiotic exposure and/or toxicity in humans.

  5. Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

    PubMed Central

    Campbell, Jerry L.; Clewell, Harvey J.; Zhou, Yi-Hui; Wright, Fred A.; Guyton, Kathryn Z.

    2014-01-01

    Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data. Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study. Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism. Results: Concentration–time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability. Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability

  6. Bio-electrosprayed living composite matrix implanted into mouse models.

    PubMed

    Jayasinghe, Suwan N; Warnes, Gary; Scotton, Chris J

    2011-10-10

    We show that composite de novo structures can be generated using bio-electrosprays. Mouse lung fibroblasts are bio-electrosprayed directly with a biopolymer to form cell-bearing matrices, which are viable even when implanted subcutaneously into murine hosts. Generated cell-bearing matrices are assessed in-vitro and found to undergo all expected cellular behaviour. Subsequent in-vivo studies demonstrate the implanted living matrices integrating as expected with the surrounding microenvironment. The in-vitro and in-vivo studies elucidate and validate the ability for either bio-electrosprays or cell electrospinning to form a desired living architecture for undergoing investigation for repairing, replacing and rejuvenating damaged and/or ageing tissues.

  7. A Systematic and Meta-Analysis of Mortality in Experimental Mouse Models Analyzing Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

    PubMed

    Kamp, Marcel A; Lieshout, Jasper H van; Dibué-Adjei, Maxine; Weber, Jasmin K; Schneider, Toni; Restin, Tanja; Fischer, Igor; Steiger, Hans-Jakob

    2017-01-30

    Animal models are established to display the pathophysiological changes following subarachnoid hemorrhage (SAH). The aim of the present study was to determine case fatality in mouse delayed cerebral ischemia (DCI) models, to compare mortality in mouse DCI models to case fatality in human SAH patients, and to identify factors influencing mouse mortality. A systematic search of the PubMed database was performed to identify all studies that assessed mouse DCI models. Mortality rates and predictor variables were extracted and compared to the human case fatality after SAH as previously reported. Predictors for mouse mortality were identified through multivariate analysis. Forty-eight studies were included in the quantitative analysis. The mean overall mortality rate was 21% in mouse DCI models. However, the time period between induction of SAH and evaluation of mortality rates is a significant variable influencing the mortality rate in mouse SAH models. The experimental SAH model was the only significant predictor for mouse mortality after 48 h. In contrast, neither the genetic background nor the anesthetic changed the case fatality rate. Mouse mortality at 24, 48, and 72 h after experimental SAH in DCI models was significantly lower than human case fatality following aneurysmal SAH. The mean overall mortality rate in mouse DCI models is significantly lower than human case fatality following aneurysmal SAH. However, time between SAH induction and evaluation is a significant variable influencing the mortality rate in mouse SAH models. Further analyses will be required to establish whether and to which extent different DCI models affect mortality and reflect human pathophysiology.

  8. Tracking Brain Palmitoylation Change: Predominance of Glial Change in a Mouse Model of Huntington Disease

    PubMed Central

    Wan, Junmei; Savas, Jeffrey N.; Roth, Amy F.; Sanders, Shaun S.; Singaraja, Roshni R.; Hayden, Michael R.; Yates, John R.; Davis, Nicholas G.

    2013-01-01

    SUMMARY Protein palmitoylation, a reversible lipid modification of proteins, is widely used in the nervous system, with dysregulated palmitoylation being implicated in a variety of neurological disorders. Described below is ABE/SILAM, a new proteomic strategy that couples acyl-biotinyl exchange (ABE) purification of palmitoyl-proteins to whole animal stable isotope labeling (SILAM) to provide an accurate tracking of palmitoylation change within rodent disease models. As a first application, we have used ABE/SILAM to look at Huntington disease (HD), profiling palmitoylation change in two HD-relevant, mouse mutants – the transgenic HD model mouse YAC128 and the hypomorphic Hip14-gt mouse, which has sharply reduced expression for HIP14 (Dhhc17), a palmitoyl-transferase implicated in the HD disease process. Rather than mapping to the degenerating neurons themselves, the biggest disease changes instead map to astrocytes and oligodendrocytes, i.e. the supporting glial cells. PMID:24211138

  9. Thinking bedside at the bench: the NOD mouse model of T1DM

    PubMed Central

    Reed, James C.; Herold, Kevan C.

    2015-01-01

    Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of β cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes. PMID:25623120

  10. A humanized microbiota mouse model of ovalbumin-induced lung inflammation.

    PubMed

    Arrieta, Marie-Claire; Sadarangani, Manish; Brown, Eric M; Russell, Shannon L; Nimmo, Michael; Dean, John; Turvey, Stuart E; Chan, Edmond S; Finlay, B Brett

    2016-07-03

    There is increasing evidence for a role of early life gut microbiota in later development of asthma in children. In our recent study, children with reduced abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia had an increased risk of development of asthma and addition of these bacteria in a humanized mouse model reduced airway inflammation. In this Addendum, we provide additional data on the use of a humanized gut microbiota mouse model to study the development of asthma in children, highlighting the differences in immune development between germ-free mice colonized with human microbes compared to those colonized with mouse gut microbiota. We also demonstrate that there is no association between the composition of the gut microbiota in older children and the diagnosis of asthma, further suggesting the importance of the gut microbiota-immune system axis in the first 3 months of life.

  11. Genetic and Statistical Analyses of Strong Selection on Polygenic Traits: What, Me Normal?

    PubMed Central

    Turelli, M.; Barton, N. H.

    1994-01-01

    We develop a general population genetic framework for analyzing selection on many loci, and apply it to strong truncation and disruptive selection on an additive polygenic trait. We first present statistical methods for analyzing the infinitesimal model, in which offspring breeding values are normally distributed around the mean of the parents, with fixed variance. These show that the usual assumption of a Gaussian distribution of breeding values in the population gives remarkably accurate predictions for the mean and the variance, even when disruptive selection generates substantial deviations from normality. We then set out a general genetic analysis of selection and recombination. The population is represented by multilocus cumulants describing the distribution of haploid genotypes, and selection is described by the relation between mean fitness and these cumulants. We provide exact recursions in terms of generating functions for the effects of selection on non-central moments. The effects of recombination are simply calculated as a weighted sum over all the permutations produced by meiosis. Finally, the new cumulants that describe the next generation are computed from the non-central moments. Although this scheme is applied here in detail only to selection on an additive trait, it is quite general. For arbitrary epistasis and linkage, we describe a consistent infinitesimal limit in which the short-term selection response is dominated by infinitesimal allele frequency changes and linkage disequilibria. Numerical multilocus results show that the standard Gaussian approximation gives accurate predictions for the dynamics of the mean and genetic variance in this limit. Even with intense truncation selection, linkage disequilibria of order three and higher never cause much deviation from normality. Thus, the empirical deviations frequently found between predicted and observed responses to artificial selection are not caused by linkage

  12. A novel animal model for pseudoxanthoma elasticum: the KK/HlJ mouse.

    PubMed

    Li, Qiaoli; Berndt, Annerose; Guo, Haitao; Sundberg, John P; Uitto, Jouni

    2012-10-01

    Pseudoxanthoma elasticum is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. A mouse model with targeted ablation of the corresponding gene (Abcc6(tm1JfK)) develops ectopic mineralization on the dermal sheath of vibrissae as biomarker of the progressive mineralization disorder. Survey of 31 mouse strains in a longitudinal aging study has identified three mouse strains with similar ectopic mineralization of the vibrissae, particularly the KK/HlJ strain. We report here that this mouse strain depicts, in addition to ectopic mineralization of the dermal sheath of vibrissae, mineral deposits in a number of internal organs. Energy dispersive X-ray analysis and topographic mapping found the presence of calcium and phosphate as the principal ions in the mineral deposits, similar to that in Abcc6(tm1JfK) mice, suggesting the presence of calcium hydroxyapatite. The mineralization was associated with a splice junction mutation at the 3' end of exon 14 of the Abcc6 gene, resulting in a 5-bp deletion from the coding region and causing frame-shift of translation. As a consequence, essentially no Abcc6 protein was detected in the liver of the KK/HlJ mice, similar to that in Abcc6(tm1JfK) mice. Collectively, our studies found that the KK/HlJ mouse strain is characterized by ectopic mineralization due to a mutation in the Abcc6 gene and therefore provides a novel model system to study pseudoxanthoma elasticum.

  13. Is the mouse a clinically relevant model for human fertilization failures?

    PubMed

    Neuber, E; Powers, R D

    2000-01-01

    This study compares failed fertilization oocytes from patients participating in an in-vitro fertilization (IVF) programme with failed fertilization oocytes from B6SJLF(1)/J mice, in order to characterize and describe the distribution of DNA in oocytes that do not undergo normal fertilization. Our goal is to evaluate the mouse IVF system as a model to gain insight into reasons for human fertilization failures. All oocytes were stained with the vital fluorescent dye, Hoechst 33342, which rapidly stains double-stranded DNA. Of the 237 human oocytes that had been scored as failed fertilization by brightfield microscopy, 61 (25.7%) showed the presence of at least one spermatozoon within the oocyte cytoplasm. In contrast, out of 69 failed fertilization mouse oocytes, only one oocyte showed the presence of a spermatozoon within its cytoplasm. Mouse failed fertilization oocytes exhibited a significantly lower internal sperm rate (P < 0.0001) than human failed fertilization oocytes. Human failed fertilization oocytes show a higher incidence of sperm penetration, but the cytoplasm fails to support pronuclear development, whereas, at least in this strain, mouse failed fertilization oocytes arise from an inability of the spermatozoa to penetrate the oocyte. This study suggests that the mouse is not a clinically relevant model for human fertilization failures.

  14. Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia

    PubMed Central

    Morini, Elisabetta; Dietrich, Paula; Salani, Monica; Downs, Heather M.; Wojtkiewicz, Gregory R.; Alli, Shanta; Brenner, Anthony; Nilbratt, Mats; LeClair, John W.; Oaklander, Anne Louise; Slaugenhaupt, Susan A.; Dragatsis, Ioannis

    2016-01-01

    Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; IkbkapΔ20/flox was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (IkbkapΔ20/flox). The TgFD9; IkbkapΔ20/flox mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect. PMID:26769677

  15. A mouse model to study infection against porcine circovirus type 2: viral distribution and lesions in mouse

    PubMed Central

    2010-01-01

    Background Little information is known about viral distribution and transmission of porcine circovirus type 2 (PCV2) in species other than swine. It is still a debated topic whether the PCV2 could be infected and caused clinical lesions. Our study is aimed to estimate the susceptibility of Kunming mouse to PCV2. Forty-eight, 6-week-old Kunming mice were randomly divided into four groups. Group A (C1-C12) was inoculated with PK-15 cell culture as a control group. Group B (sPCV1-12) was inoculated orally and intramuscularly with PCV2 (106.2TCID50/ml). Group C (mPCV1-12) was inoculated orally and intramuscularly with PCV2 (106.2TCID50/ml) and a booster inoculation at days 14 and 28 after the first inoculation. Group D (MixPCV1-12) was unvaccinated but released into Group C. Each group was sacrificed at 7, 14, 28, and 42 days post-inoculation, respectively. Necropsy was checked on every mouse. Sera samples were collected for the test of PCV2 specific antibody. Tissues were collected for histopathology study and polymerase chain reaction (PCR). Results The results showed that viral replication, seroconversion, and microscopic lesions were found in inoculated mice. Continuous existence of PCV2 viruses in lymph nodes have been confirmed by PCR, which took at least seven days for the virus to be transferred into other organs from the primary interface, and the diffusion to thymus had been retarded for seven days. Special PCV2 antibody could be found in PCV2 inoculation mice and was significantly higher than that in the control. Further more, microscopic lesions and the main target of PCV2 focused in the lymph nodes with a characteristic depletion and occasional necrosis of lymphocytes in the cortex and paracortex were found in inoculated mice. Conclusions The Kunming mouse could be infected by PCV2 virus and used as a PCV2 infected experimental model. PMID:20630105

  16. Evaluation of synthetic vascular grafts in a mouse carotid grafting model

    PubMed Central

    Tan, Richard P.; Michael, Praveesuda L.; Lee, Bob S. L.; Vanags, Laura Z.; Ng, Martin K. C.; Bursill, Christina A.; Wise, Steven G.

    2017-01-01

    Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance. PMID:28355300

  17. A new transgenic mouse model for conditional overexpression of the Polycomb Group protein EZH2.

    PubMed

    Koppens, Martijn A J; Tanger, Ellen; Nacerddine, Karim; Westerman, Bart; Song, Ji-Ying; van Lohuizen, Maarten

    2017-04-01

    The Polycomb Group protein EZH2 is upregulated in most prostate cancers, and its overexpression is associated with poor prognosis. Most insights into the functional role of EZH2 in prostate cancer have been gained using cell lines and EZH2 inactivation studies. However, the question remains whether overexpression of EZH2 can initiate prostate tumourigenesis or drive tumour progression. Appropriate transgenic mouse models that are required to answer such questions are lacking. We developed one such transgenic mouse model for conditional overexpression of Ezh2. In this transgene, Ezh2 and Luciferase are transcribed from a single open reading frame. The latter gene enables intravital bioluminescent imaging of tissues expressing this transgene, allowing the detection of tumour outgrowth and potential metastatic progression over time. Prostate-specific Ezh2 overexpression by crossbreeding with Probasin-Cre mice led to neoplastic prostate lesions at low incidence and with a long latency. Compounding a previously described Bmi1-transgene and Pten-deficiency prostate cancer mouse model with the Ezh2 transgene did not enhance tumour progression or drive metastasis formation. In conclusion, we here report the generation of a wildtype Ezh2 overexpression mouse model that allows for intravital surveillance of tissues with activated transgene. This model will be an invaluable tool for further unravelling the role of EZH2 in cancer.

  18. Basal glycogenolysis in mouse skeletal muscle: in vitro model predicts in vivo fluxes

    NASA Technical Reports Server (NTRS)

    Lambeth, Melissa J.; Kushmerick, Martin J.; Marcinek, David J.; Conley, Kevin E.

    2002-01-01

    A previously published mammalian kinetic model of skeletal muscle glycogenolysis, consisting of literature in vitro parameters, was modified by substituting mouse specific Vmax values. The model demonstrates that glycogen breakdown to lactate is under ATPase control. Our criteria to test whether in vitro parameters could reproduce in vivo dynamics was the ability of the model to fit phosphocreatine (PCr) and inorganic phosphate (Pi) dynamic NMR data from ischemic basal mouse hindlimbs and predict biochemically-assayed lactate concentrations. Fitting was accomplished by optimizing four parameters--the ATPase rate coefficient, fraction of activated glycogen phosphorylase, and the equilibrium constants of creatine kinase and adenylate kinase (due to the absence of pH in the model). The optimized parameter values were physiologically reasonable, the resultant model fit the [PCr] and [Pi] timecourses well, and the model predicted the final measured lactate concentration. This result demonstrates that additional features of in vivo enzyme binding are not necessary for quantitative description of glycogenolytic dynamics.

  19. Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models.

    PubMed

    Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min; Shen, Michael M; Abate-Shen, Cory; Califano, Andrea

    2015-09-29

    Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.

  20. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models

    PubMed Central

    Zuo, Bingfeng; Gao, Xianjun; Zhang, Ti; Du, Zhi; Wu, Chenxuan; Yin, HaiFang

    2016-01-01

    Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters—the latency period, take rates, pathological features and metastatic rates—were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study

  1. Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

  2. Histological study of masseter muscle in a mouse muscular dystrophy model (mdx mouse).

    PubMed

    Abe, S; Kasahara, N; Amano, M; Yoshii, M; Watanabe, H; Ide, Y

    2000-08-01

    Histological changes in the masseter muscle were observed over time in mdx mice, a muscular dystrophy model. It was found that marked necrosis occurs about the time of weaning at around 4 weeks of age; then the tissue actively regenerates at 8 weeks and stabilizes as regenerated muscle with centronuclei at 15 weeks old. This study examined the centronucleus in regenerated muscle. The process from necrosis to regeneration in muscle fibers occurs a little later in the masseter muscle than in other limbic muscles. Regenerated muscles observed around 15 weeks after birth showed a moth-eaten appearance. Transmission Electron Microscope (TEM) observation of transverse sections of muscle fibers revealed that myofibrils surrounded lost regions in the area showing a moth-eaten appearance. Thus, some defensive mechanism may affect the ability of muscle fibers to maintain a function close to normal in mdx mice even though the muscle fibers develop muscular dystrophy. The function of the masseter muscle drastically changes from sucking to mastication behavior at around 4 weeks, and this was considered to influence the morphological changes in the muscle tissue. The moth-eaten appearance seen at 15 weeks may represent an appropriate myofibril reconstruction preventing invasion of the lost regions.

  3. Time to Integrate to Nest Test Evaluation in a Mouse DSS-Colitis Model

    PubMed Central

    Häger, Christine; Keubler, Lydia M.; Biernot, Svenja; Dietrich, Jana; Buchheister, Stephanie; Buettner, Manuela; Bleich, André

    2015-01-01

    Severity assessment in laboratory animals is an important issue regarding the implementation of the 3R concept into biomedical research and pivotal in current EU regulations. In mouse models of inflammatory bowel disease severity assessment is usually undertaken by clinical scoring, especially by monitoring reduction of body weight. This requires daily observance and handling of each mouse, which is time consuming, stressful for the animal and necessitates an experienced observer. The time to integrate to nest test (TINT) is an easily applicable test detecting disturbed welfare by measuring the time interval mice need to integrate nesting material to an existing nest. Here, TINT was utilized to assess severity in a mouse DSS-colitis model. TINT results depended on the group size of mice maintained per cage with most consistent time intervals measured when co-housing 4 to 5 mice. Colitis was induced with 1% or 1.5% DSS in group-housed WT and Cd14-deficient mice. Higher clinical scores and loss of body weight were detected in 1.5% compared to 1% DSS treated mice. TINT time intervals showed no dose dependent differences. However, increased clinical scores, body weight reductions, and increased TINT time intervals were detected in Cd14-/- compared to WT mice revealing mouse strain related differences. Therefore, TINT is an easily applicable method for severity assessment in a mouse colitis model detecting CD14 related differences, but not dose dependent differences. As TINT revealed most consistent results in group-housed mice, we recommend utilization as an additional method substituting clinical monitoring of the individual mouse. PMID:26637175

  4. Time to Integrate to Nest Test Evaluation in a Mouse DSS-Colitis Model.

    PubMed

    Häger, Christine; Keubler, Lydia M; Biernot, Svenja; Dietrich, Jana; Buchheister, Stephanie; Buettner, Manuela; Bleich, André

    2015-01-01

    Severity assessment in laboratory animals is an important issue regarding the implementation of the 3R concept into biomedical research and pivotal in current EU regulations. In mouse models of inflammatory bowel disease severity assessment is usually undertaken by clinical scoring, especially by monitoring reduction of body weight. This requires daily observance and handling of each mouse, which is time consuming, stressful for the animal and necessitates an experienced observer. The time to integrate to nest test (TINT) is an easily applicable test detecting disturbed welfare by measuring the time interval mice need to integrate nesting material to an existing nest. Here, TINT was utilized to assess severity in a mouse DSS-colitis model. TINT results depended on the group size of mice maintained per cage with most consistent time intervals measured when co-housing 4 to 5 mice. Colitis was induced with 1% or 1.5% DSS in group-housed WT and Cd14-deficient mice. Higher clinical scores and loss of body weight were detected in 1.5% compared to 1% DSS treated mice. TINT time intervals showed no dose dependent differences. However, increased clinical scores, body weight reductions, and increased TINT time intervals were detected in Cd14-/- compared to WT mice revealing mouse strain related differences. Therefore, TINT is an easily applicable method for severity assessment in a mouse colitis model detecting CD14 related differences, but not dose dependent differences. As TINT revealed most consistent results in group-housed mice, we recommend utilization as an additional method substituting clinical monitoring of the individual mouse.

  5. The ataxic mouse as a model for studying downbeat nystagmus

    PubMed Central

    Stahl, John S.; Thumser, Zachary C.; Oommen, Brian S.

    2016-01-01

    Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice. PMID:23302704

  6. New Mouse Model May Aid in Developing Effective Therapies for Ovarian Cancer | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer A new genetically engineered mouse model appears promising as an effective tool for preclinical testing of novel therapies for ovarian cancer, which tends to be diagnosed in late stage. There are few effective treatments for the disease.

  7. Comparative Exposure to Soy Biodiesel Emissions in an Allergic Mouse Model

    EPA Science Inventory

    We assessed the immunological effects following inhalation of emissions from 100% Soy biodiesel (S100) or a 20% mix with conventional petrodiesel (S20), in a house dust mite (HDM) allergic Balb/cJ mouse model. Female mice (8/group) were exposed whole body (4 hr/d, 5 d/wk, 4wk) to...

  8. Developing a Mouse Model of Sensory and Cognitive Deficits for Multiple Sclerosis

    DTIC Science & Technology

    2012-07-01

    neurotransmitter systems. KEY RESEARCH ACCOMPLISHMENTS 1. Homologous recombination in mouse embryonic stem cells to generate an inducible...focus on cognitive dysfunction associated with defective myelin. We have developed this model using homologous recombination in embryonic stem cells ...our progress toward completion of our goals. We have now repeated the homologous recombinant experiments and are screening for embryonic stem cell

  9. Genetic markers of wheat (Triticum aestivum) associated with flavor preference using a mouse (Mus musculus) model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Whole wheat products provide critical nutrients for human health, differences in wheat flavor are not well understood. Using the house mouse as a model system, flavor preference and discrimination were examined using a two-choice feeding system and 24-h trials and the Student’s t statistic. To elimi...

  10. Activity-Dependent Changes in MAPK Activation in the Angelman Syndrome Mouse Model

    ERIC Educational Resources Information Center

    Filonova, Irina; Trotter, Justin H.; Banko, Jessica L.; Weeber, Edwin J.

    2014-01-01

    Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal "UBE3A" gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular…

  11. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models.

    PubMed

    Osman, Erkan Y; Miller, Madeline R; Robbins, Kate L; Lombardi, Abby M; Atkinson, Arleigh K; Brehm, Amanda J; Lorson, Christian L

    2014-09-15

    Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of Survival Motor Neuron-1 (SMN1). In all SMA patients, a nearly identical copy gene called SMN2 is present, which produces low levels of functional protein owing to an alternative splicing event. To prevent exon-skipping, we have targeted an intronic repressor, Element1 (E1), located upstream of SMN2 exon 7 using Morpholino-based antisense oligonucleotides (E1(MO)-ASOs). A single intracerebroventricular injection in the relatively severe mouse model of SMA (SMNΔ7 mouse model) elicited a robust induction of SMN protein, and mean life span was extended from an average survival of 13 to 54 days following a single dose, consistent with large weight gains and a correction of the neuronal pathology. Additionally, E1(MO)-ASO treatment in an intermediate SMA mouse (SMN(RT) mouse model) significantly extended life span by ∼700% and weight gain was comparable with the unaffected animals. While a number of experimental therapeutics have targeted the ISS-N1 element of SMN2 pre-mRNA, the development of E1 ASOs provides a new molecular target for SMA therapeutics that dramatically extends survival in two important pre-clinical models of disease.

  12. Identifying genetic markers of wheat (Triticum aestivum) associated with flavor preference using a mouse model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Whole wheat products provide critical nutrients for human health, though differences in wheat flavor are not well understood. Using the house mouse as a model system, flavor was examined using a two-choice feeding system and the Student’s t statistic. To eliminate the confounding effect of processin...

  13. Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders.

    DTIC Science & Technology

    1999-10-01

    This study aims to determine what roles bioenergetic dysfunction and oxidative stress play in the etiology of neurodegeneration in Huntington’s ... disease (HE) and familial amyotrophic lateral sclerosis (FALS), using transgenic mouse models. Studies in this first year employed C-14-2-deoxyglucose in

  14. An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

    PubMed Central

    Reiberger, Thomas; Chen, Yunching; Ramjiawan, Rakesh R; Hato, Tai; Fan, Christopher; Samuel, Rekha; Roberge, Sylvie; Huang, Peigen; Lauwers, Gregory Y; Zhu, Andrew X; Bardeesy, Nabeel; Jain, Rakesh K; Duda, Dan G

    2016-01-01

    Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4−/−Stk3F/− (also known as Mst1−/−Mst2F/−; F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis. PMID:26203823

  15. Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines

    PubMed Central

    Puzzo, Daniela; Lee, Linda; Palmeri, Agostino; Calabrese, Giorgio; Arancio, Ottavio

    2014-01-01

    In Alzheimer’s disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology – assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice – contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms. PMID:24462904

  16. Mouse models of graft-versus-host disease: advances and limitations

    PubMed Central

    Schroeder, Mark A.; DiPersio, John F.

    2011-01-01

    The limiting factor for successful hematopoietic stem cell transplantation (HSCT) is graft-versus-host disease (GvHD), a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT) that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future. PMID:21558065

  17. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  18. Comparative mRNA analysis of behavioral and genetic mouse models of aggression.

    PubMed

    Malki, Karim; Tosto, Maria G; Pain, Oliver; Sluyter, Frans; Mineur, Yann S; Crusio, Wim E; de Boer, Sietse; Sandnabba, Kenneth N; Kesserwani, Jad; Robinson, Edward; Schalkwyk, Leonard C; Asherson, Philip

    2016-04-01

    Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors.

  19. The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men.

    SciTech Connect

    Lehman, J M; Michaud III, Edward J; Schoeb, T; Aydin Son, Yesim; Miller, M; Yoder, Bradley

    2008-08-01

    The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive polycystic kidney disease. The ORPK mouse arose through integration of a transgene into an intron of the Ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Furthermore, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner's syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle.

  20. The Oak Ridge Polycystic Kidney Mouse: Modeling Ciliopathies of Mice and Men

    PubMed Central

    Lehman, Jonathan M.; Michaud, Edward J.; Schoeb, Trenton R.; Aydin-Son, Yesim; Miller, Michael; Yoder, Bradley K.

    2009-01-01

    The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive Polycystic Kidney Disease. The ORPK mouse arose through integration of a transgene into an intron of the ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Further, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner’s syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle. PMID:18366137

  1. Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.

    PubMed

    Sydow, Astrid; Van der Jeugd, Ann; Zheng, Fang; Ahmed, Tariq; Balschun, Detlef; Petrova, Olga; Drexler, Dagmar; Zhou, Lepu; Rune, Gabriele; Mandelkow, Eckhard; D'Hooge, Rudi; Alzheimer, Christian; Mandelkow, Eva-Maria

    2011-11-01

    The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.

  2. Therapeutic Effects of Resveratrol in a Mouse Model of LPS and Cigarette Smoke-Induced COPD.

    PubMed

    Chen, Jinlong; Yang, Xu; Zhang, Weiya; Peng, Danhua; Xia, Yanan; Lu, Yi; Han, Xiaodong; Song, Guangjie; Zhu, Jing; Liu, Renping

    2016-12-01

    This study was designed to examine whether resveratrol exerts the protective effects on LPS and cigarette smoke (LC)-induced COPD in a murine model. In lung histopathological studies, H&E, Masson's trichrome, and AB-PAS staining were performed. The cytokines (IL-6, IL-17, TGF-β, and TNF-α) and inflammatory cells in BALF were determined. The Beclin1 level in the lungs of mouse was analyzed. Compared with the LC-induced mouse, the level of inflammatory cytokines (IL-17, IL-6, TNF-α, and TGF-β) of the BALF in the resveratrol + cigarette smoke-treated mouse had obviously decreased. Histological examination of the lung tissue revealed that the resveratrol treatment attenuated the fibrotic response and mucus hypersecretion. In addition, resveratrol inhibited the expression of the Beclin1 protein in mouse lungs. The presented findings collectively suggest that resveratrol has a therapeutic effect on mouse LC-induced COPD, and its mechanism of action might be related to reducing the production of the Beclin1 protein.

  3. Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

    PubMed

    Koontz, Bridget F; Verhaegen, Frank; De Ruysscher, Dirk

    2017-01-01

    Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation.

  4. Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia.

    PubMed

    Strom, T M; Francis, F; Lorenz, B; Böddrich, A; Econs, M J; Lehrach, H; Meitinger, T

    1997-02-01

    X-linked hypophosphatemic rickets in humans is caused by mutations in the PEX gene which codes for a protein homologous to neutral endopeptidases. Hyp and Gy mice both have X-linked hypophosphatemic rickets, although genetic data and the different phenotypic spectra observed have previously suggested that two different genes are mutated. In addition to the metabolic disorder observed in Hyp mice, male Gy mice are sterile and show circling behavior and reduced viability. We now report the cloning of the mouse homolog of PEX which is highly conserved between man and mouse. The 3' end of this gene is deleted in Hyp mice. In Gy mice, the first three exons and the promotor region are deleted. Thus, Hyp and Gy are allelic mutations and both provide mouse models for X-linked hypophosphatemia.

  5. Excavating the Genome: Large Scale Mutagenesis Screening for the Discovery of New Mouse Models

    PubMed Central

    Sundberg, John P.; Dadras, Soheil S.; Silva, Kathleen A.; Kennedy, Victoria E.; Murray, Stephen A.; Denegre, James; Schofield, Paul N.; King, Lloyd E.; Wiles, Michael; Pratt, C. Herbert

    2016-01-01

    Technology now exists for rapid screening of mutated laboratory mice to identify phenotypes associated with specific genetic mutations. Large repositories exist for spontaneous mutants and those induced by chemical mutagenesis, many of which have never been studied or comprehensively evaluated. To supplement these resources, a variety of techniques have been consolidated in an international effort to create mutations in all known protein coding genes in the mouse. With targeted embryonic stem cell lines now available for almost all protein coding genes and more recently CRISPR/Cas9 technology, large-scale efforts are underway to create novel mutant mouse strains and to characterize their phenotypes. However, accurate diagnosis of skin, hair, and nail diseases still relies on careful gross and histological analysis. While not automated to the level of the physiological phenotyping, histopathology provides the most direct and accurate diagnosis and correlation with human diseases. As a result of these efforts, many new mouse dermatological disease models are being developed. PMID:26551941

  6. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    PubMed Central

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  7. Construction of a mouse model of factor VIII deficiency by gene targeting

    SciTech Connect

    Bi, L.; Lawler, A.; Gearhart, J.

    1994-09-01

    To develop a small animal model of hemophilia A for gene therapy experiments, we set out to construct a mouse model for factor VIII deficiency by gene targeting. First, we screened a mouse liver cDNA library using a human FVIII cDNA probe. We cloned a 2.6 Kb partial mouse factor VIII cDNA which extends from 800 base pairs of the 3{prime} end of exon 14 to the 5{prime} end of exon 26. A mouse genomic library made from strain 129 was then screened to obtain genomic fragments covering the exons desired for homologous recombination. Two genomic clones were obtained, and one covering exon 15 through 22 was used for gene targeting. To make gene targeting constructs, a 5.8 Kb genomic DNA fragment covering exons 15 to 19 of the mouse FVIII gene was subcloned, and the neo expression cassette was inserted into exons 16 and 17 separately by different strategies. These two constructs were named MFVIIIC-16 and MFVIIIC-17. The constructs were linearized and transfected into strain 129 mouse ES cells by electroporation. Factor VIII gene-knockout ES cell lines were selected by G-418 and screened by genomic Southern blots. Eight exon 16 targeted cell lines and five exon 17 targeted cell lines were obtained. Three cell lines from each construct were injected into blastocysts and surgically transferred into foster mothers. Multiple chimeric mice with 70-90% hair color derived from the ES-cell genotype were seen with both constructs. Germ line transmission of the ES-cell genotype has been obtained for the MFVIIIC-16 construct, and multiple hemophilia A carrier females have been identified. Factor VIII-deficient males will be conceived soon.

  8. A Novel Mouse Model of a Patient Mucolipidosis II Mutation Recapitulates Disease Pathology*

    PubMed Central

    Paton, Leigh; Bitoun, Emmanuelle; Kenyon, Janet; Priestman, David A.; Oliver, Peter L.; Edwards, Benjamin; Platt, Frances M.; Davies, Kay E.

    2014-01-01

    Mucolipidosis II (MLII) is a lysosomal storage disorder caused by loss of N-acetylglucosamine-1-phosphotransferase, which tags lysosomal enzymes with a mannose 6-phosphate marker for transport to the lysosome. In MLII, the loss of this marker leads to deficiency of multiple enzymes and non-enzymatic proteins in the lysosome, leading to the storage of multiple substrates. Here we present a novel mouse model of MLII homozygous for a patient mutation in the GNPTAB gene. Whereas the current gene knock-out mouse model of MLII lacks some of the characteristic features of the human disease, our novel mouse model more fully recapitulates the human pathology, showing growth retardation, skeletal and facial abnormalities, increased circulating lysosomal enzymatic activities, intracellular lysosomal storage, and reduced life span. Importantly, MLII behavioral deficits are characterized for the first time, including impaired motor function and psychomotor retardation. Histological analysis of the brain revealed progressive neurodegeneration in the cerebellum with severe Purkinje cell loss as the underlying cause of the ataxic gait. In addition, based on the loss of Npc2 (Niemann-Pick type C 2) protein expression in the brain, the mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of Niemann-Pick type C disease. No improvement in brain pathology was observed. This indicates that cerebellar degeneration is not primarily triggered by loss of Npc2 function. This study emphasizes the value of modeling MLII patient mutations to generate clinically relevant mouse mutants to elucidate the pathogenic molecular pathways of MLII and address their amenability to therapy. PMID:25107912

  9. Delayed myelination in a mouse model of fragile X syndrome.

    PubMed

    Pacey, Laura K K; Xuan, Ingrid C Y; Guan, Sihui; Sussman, Dafna; Henkelman, R Mark; Chen, Yan; Thomsen, Christian; Hampson, David R

    2013-10-01

    Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRα+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.

  10. Strontium biokinetic model for mouse-like rodent.

    PubMed

    Malinovsky, Georgy; Yarmoshenko, Ilia; Zhukovsky, Michael; Starichenko, Vera; Modorov, Makar

    2013-04-01

    Model describing the biokinetics of strontium for murine rodent is suggested. The model represents modification of the ICRP model for reference human with reduced number of compartments: Blood, Gastrointestinal tract, Soft tissues, Skeleton, Urinary bladder. To estimate transfer rates of the model the published experimental data on strontium retention in body of laboratory and wild mice were analyzed. A set of eleven transfer rates suggested for the strontium biokinetic model for murine rodent satisfactorily describes both the laboratory experiments (relative standard error of 9.5%) and data on radiostrontium content available for wild animals. Application of the model allows estimation of strontium distribution by organs and tissues both in the cases of acute and chronic exposure with assessment of strontium activity in organs with time since beginning of exposure. The developed strontium biokinetic model will be used for internal dose assessment for murine rodents inhabiting East-Ural Radioactive Trace, where (90)Sr intake is a significant source of contemporary internal exposure.

  11. Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models.

    PubMed

    Osborne, Melissa; Gomez, Daniel; Feng, Zhihua; McEwen, Corissa; Beltran, Jose; Cirillo, Kim; El-Khodor, Bassem; Lin, Ming-Yi; Li, Yun; Knowlton, Wendy M; McKemy, David D; Bogdanik, Laurent; Butts-Dehm, Katherine; Martens, Kimberly; Davis, Crystal; Doty, Rosalinda; Wardwell, Keegan; Ghavami, Afshin; Kobayashi, Dione; Ko, Chien-Ping; Ramboz, Sylvie; Lutz, Cathleen

    2012-10-15

    A number of mouse models for spinal muscular atrophy (SMA) have been genetically engineered to recapitulate the severity of human SMA by using a targeted null mutation at the mouse Smn1 locus coupled with the transgenic addition of varying copy numbers of human SMN2 genes. Although this approach has been useful in modeling severe SMA and very mild SMA, a mouse model of the intermediate form of the disease would provide an additional research tool amenable for drug discovery. In addition, many of the previously engineered SMA strains are multi-allelic by design, containing a combination of transgenes and targeted mutations in the homozygous state, making further genetic manipulation difficult. A new genetic engineering approach was developed whereby variable numbers of SMN2 sequences were incorporated directly into the murine Smn1 locus. Using combinations of these alleles, we generated an allelic series of SMA mouse strains harboring no, one, two, three, four, five, six or eight copies of SMN2. We report here the characterization of SMA mutants in this series that displayed a range in disease severity from embryonic lethal to viable with mild neuromuscular deficits.

  12. Application of genetically altered models as replacement for the lifetime mouse bioassay in pharmaceutical development.

    PubMed

    Alden, Carl; Smith, Peter; Morton, Dan

    2002-01-01

    The international pharmaceutical regulatory academic and industrial toxicology communities are collaborating to improve the efficiency and effectiveness of cancer hazard identification based on dramatic improvements in our understanding of the cancer process. Guidelines emanating from the International Conference on Harmonization provide for use of in vivo alternatives. Standard practices utilizing lifetime rat and mouse studies are recognized as seriously flawed with over 80% false positive rates. Furthermore, tobacco, the most important human carcinogen commercialized by industry, is negative in these traditional lifetime studies. The lifetime mouse bioassay is generally recognized in pharmaceutical development as not adding value in safety assessment. An international consortium under the aegis of ILSI has recently completed an evaluation of alternative mouse cancer models. Transgenic models are less expensive, use fewer animals and take less time than traditional lifetime bioassays. These alternative models have now been sufficiently evaluated to be considered useful in the safety assessment plan for pharmaceuticals in development. Specifically for example, the rasH2 appears useful in detecting nongenotoxic as well as genotoxic rodent tumorigens with improved concordance with human response. The p53+/- heterozygous mouse apparently identifies hormonal carcinogenic mechanisms, immunosuppressive carcinogens, and genotoxic carcinogens. The TG:AC predicts for rodent tumorigens applied topically. Recent experiences at FDA, CPMP, and MHW indicate that with good planning and agency interactions, regulatory acceptability can be anticipated.

  13. The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development.

    PubMed

    Vulin, Adeline; Wein, Nicolas; Simmons, Tabatha R; Rutherford, Andrea M; Findlay, Andrew R; Yurkoski, Jacqueline A; Kaminoh, Yuuki; Flanigan, Kevin M

    2015-11-01

    Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping.

  14. Development of the Nonobese Diabetic Mouse and Contribution of Animal Models for Understanding Type 1 Diabetes

    PubMed Central

    Mullen, Yoko

    2017-01-01

    Abstract In 1974, the discovery of a mouse and a rat that spontaneously developed hyperglycemia led to the development of 2 autoimmune diabetes models: nonobese diabetic (NOD) mouse and Bio-Breeding rat. These models have contributed to our understanding of autoimmune diabetes, provided tools to dissect autoimmune islet damage, and facilitated development of early detection, prevention, and treatment of type 1 diabetes. The genetic characterization, monoclonal antibodies, and congenic strains have made NOD mice especially useful. Although the establishment of the inbred NOD mouse strain was documented by Makino et al (Jikken Dobutsu. 1980;29:1–13), this review will focus on the not-as-well-known history leading to the discovery of a glycosuric female mouse by Yoshihiro Tochino. This discovery was spearheaded by years of effort by Japanese scientists from different disciplines and dedicated animal care personnel and by the support of the Shionogi Pharmaceutical Company, Osaka, Japan. The history is based on the early literature, mostly written in Japanese, and personal communications especially with Dr Tochino, who was involved in diabetes animal model development and who contributed to the release of NOD mice to the international scientific community. This article also reviews the scientific contributions made by the Bio-Breeding rat to autoimmune diabetes. PMID:28291161

  15. Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts

    PubMed Central

    Whalley, H C; Adams, M J; Hall, L S; Clarke, T-K; Fernandez-Pujals, A M; Gibson, J; Wigmore, E; Hafferty, J; Hagenaars, S P; Davies, G; Campbell, A; Hayward, C; Lawrie, S M; Porteous, D J; Deary, I J; McIntosh, A M

    2016-01-01

    Major depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterized by low mood, psychomotor slowing and increased levels of the personality trait neuroticism; factors also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. The presence of SCZ-like MDD subgroups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. Here, we hypothesized that higher SCZ polygenic risk would define larger MDD case–control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PRSs) for SCZ and their association with cognitive variables, neuroticism, mood and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). The individuals were divided into those with, and without, depression (n=2587 and n=16 764, respectively) to test for the interactions between MDD status and schizophrenia risk. Replication was sought in UK Biobank (UKB; n=6049 and n=27 476 cases and controls, respectively). In both the cohorts, we found significant interactions between SCZ-PRS and MDD status for measures of psychological distress (βGS=−0.04, PGS=0.014 and βUKB=−0.09, PUKB⩽0.001 for GS:SFHS and UKB, respectively) and neuroticism (βGS=−0.04, PGS=0.002 and βUKB=−0.06, PUKB=0.023). In both the cohorts, there was a reduction of case–control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ. PMID:27801894

  16. Association of polygenic risk for major psychiatric illness with subcortical volumes and white matter integrity in UK Biobank

    PubMed Central

    Reus, L. M.; Shen, X.; Gibson, J.; Wigmore, E.; Ligthart, L.; Adams, M. J.; Davies, G.; Cox, S. R.; Hagenaars, S. P.; Bastin, M. E.; Deary, I. J.; Whalley, H. C.; McIntosh, A. M.

    2017-01-01

    Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BP) are common, disabling and heritable psychiatric diseases with a complex overlapping polygenic architecture. Individuals with these disorders, as well as their unaffected relatives, show widespread structural differences in corticostriatal and limbic networks. Structural variation in many of these brain regions is also heritable and polygenic but whether their genetic architecture overlaps with that of major psychiatric disorders is unknown. We sought to address this issue by examining the impact of polygenic risk of MDD, SCZ, and BP on subcortical brain volumes and white matter (WM) microstructure in a large single sample of neuroimaging data; the UK Biobank Imaging study. The first release of UK Biobank imaging data comprised participants with overlapping genetic data and subcortical volumes (N = 978) and WM measures (N = 816). The calculation of polygenic risk scores was based on genome-wide association study results generated by the Psychiatric Genomics Consortium. Our findings indicated no statistically significant associations between either subcortical volumes or WM microstructure, and polygenic risk for MDD, SCZ or BP. These findings suggest that subcortical brain volumes and WM microstructure may not be closely linked to the genetic mechanisms of major psychiatric disorders. PMID:28186152

  17. Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model

    PubMed Central

    Psotta, Laura; Rockahr, Carolin; Gruss, Michael; Kirches, Elmar; Braun, Katharina; Lessmann, Volkmar; Bock, Jörg; Endres, Thomas

    2015-01-01

    There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in Alzheimer’s disease (AD) pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF+/−). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis revealed that the APP/PS1-BDNF+/−-mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF+/−-mice. However in the Morris water maze (MWM) test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pathology in the APP/PS1 and APP/PS1-BDNF+/−-mice and observed a comparable plaque density in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF+/−-mice further supports the hypothesis that BDNF deficiency

  18. Molecular and clinical implementations of ovarian cancer mouse avatar models

    PubMed Central

    Zayed, Amira A.; Mandrekar, Sumithra J.; Haluska, Paul

    2016-01-01

    Innovation in oncology drug development has been hindered by lack of preclinical models that reliably predict clinical activity of novel therapies in cancer patients. Increasing desire for individualize treatment of patients with cancer has led to an increase in the use of patient-derived xenografts (PDX) engrafted into immune-compromised mice for preclinical modeling. Large numbers of tumor-specific PDX models have been established and proved to be powerful tools in pre-clinical testing. A subset of PDXs, referred to as Avatars, establish tumors in an orthotopic and treatment naïve fashion that may represent the most clinical relevant model of individual human cancers. This review will discuss ovarian cancer (OC) PDX models demonstrating the opportunities and limitations of these models in cancer drug development, and describe concepts of clinical trials design in Avatar guided therapy. PMID:26408297

  19. A physiological systems approach to modeling and resetting of mouse thermoregulation under heat stress.

    PubMed

    Grosman, Benyamin; Shaik, Osman S; Helwig, Bryan G; Leon, Lisa R; Doyle, Francis J

    2011-09-01

    Heat stroke (HS) is a serious civilian and military health issue. Due to the limited amount of experimental data available in humans, this study was conducted on a mouse mathematical model fitted on experimental data collected from mice under HS conditions, with the assumption there is good agreement among mammals. Core temperature (T(c)) recovery responses in a mouse model consist of hypothermia and delayed fever during 24 h of recovery that represent potential biomarkers of HS severity. The objective of this study was to develop a simulation model of mouse T(c) responses and identify optimal treatment windows for HS recovery using a three-dimensional predictive heat transfer simulation model. Several bioenergetic simulation variables, including nonlinear metabolic heat production (W/m³), temperature-dependent convective heat transfer through blood mass perfusion (W/m³), and activity-related changes in circadian T(c) were used for model simulation. The simulation results predicted the experimental data with few disparities. Using this simulation model, we tested a series of ambient temperature treatment strategies to minimize hypothermia and delayed fever to accelerate HS recovery. Using a genetic algorithm, we identified eight time segments (ambient temperature = 27, 30, 31, 29, 28, 28, 27, 26°C) of 110 min total duration that optimized HS recovery in our model simulation.

  20. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

    PubMed

    Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D; Bell, Aaron J; Chambers, Daniel B; Hinchey, Joseph; Choi, Richard J; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J; Ferrick, Neal J; Terlizzi, Allison M; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A; Zukin, R Suzanne; Woo, Newton H; Tranfaglia, Michael R; Louneva, Natalia; Arnold, Steven E; Siegel, Steven J; Bolduc, Francois V; McDonald, Thomas V; Jongens, Thomas A; McBride, Sean M J

    2015-01-07

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

  1. PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome

    PubMed Central

    Choi, Catherine H.; Schoenfeld, Brian P.; Weisz, Eliana D.; Bell, Aaron J.; Chambers, Daniel B.; Hinchey, Joseph; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J.; Ferrick, Neal J.; Terlizzi, Allison M.; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A.; Zukin, R. Suzanne; Woo, Newton H.; Tranfaglia, Michael R.; Louneva, Natalia; Arnold, Steven E.; Siegel, Steven J.

    2015-01-01

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS. PMID:25568131

  2. Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model

    PubMed Central

    Cheemarla, Nagarjuna R.; Guerrero-Plata, Antonieta

    2015-01-01

    Human Metapneumovirus (hMPV) is a leading respiratory viral pathogen associated with bronchiolitis, pneumonia, and asthma exacerbation in young children, the elderly and immunocompromised individuals. The development of a potential vaccine against hMPV requires detailed understanding of the host immune system, which plays a significant role in hMPV pathogenesis, susceptibility and vaccine efficacy. As a result, animal models have been developed to better understand the mechanisms by which hMPV causes disease. Several animal models have been evaluated and established so far to study the host immune responses and pathophysiology of hMPV infection. However, inbred laboratory mouse strains have been one of the most used animal species for experimental modeling and therefore used for the studies of immunity and immunopathogenesis to hMPV. This review summarizes the contributions of the mouse model to our understanding of the immune response against hMPV infection. PMID:26393657

  3. Catheterization of the gallbladder: A novel mouse model of severe acute cholangitis

    PubMed Central

    Yu, Jian-Hua; Tang, Hai-Jun; Zhang, Wei-Guang; Zhu, Zhi-Yang; Ruan, Xin-Xian; Lu, Bao-Chun

    2017-01-01

    AIM To establish a severe acute cholangitis (SAC) model in mice. METHODS Cholecystic catheterization was performed under the condition of bile duct ligation (BDL). Trans-cholecystic injection of lipopolysaccharide (LPS) was defined as the SAC animal model. Sham operation group, intraperitoneal injection of LPS without BDL group, intraperitoneal injection of LPS with BDL group and trans-cholecystic injection of normal saline with BDL group were defined as control groups. The survival rates and tissue injuries in liver, lungs and kidney were evaluated. RESULTS Mice in the SAC group showed a time-dependent mortality and much more severe tissue injuries in liver, lungs and kidney, compared with other groups. However, relieving biliary obstruction could effectively reduce mortality and attenuate liver injury in the SAC mouse model. CONCLUSION Trans-cholecystic injection of LPS under the condition of biliary obstruction could establish a repeatable and reversible mouse model of SAC. PMID:28348482

  4. Histopathological Evaluation of Skeletal Muscle with Specific Reference to Mouse Models of Muscular Dystrophy.

    PubMed

    Terry, Rebecca L; Wells, Dominic J

    2016-12-01

    The muscular dystrophies are a diverse group of degenerative diseases for which many mouse models are available. These models are frequently used to assess potential therapeutic interventions and histological evaluation of multiple muscles is an important part of this assessment. Histological evaluation is especially useful when combined with tests of muscle function. This unit describes a protocol for necropsy, processing, cryosectioning, and histopathological evaluation of murine skeletal muscles, which is applicable to both models of muscular dystrophy and other neuromuscular conditions. Key histopathological features of dystrophic muscle are discussed using the mdx mouse (a model of Duchenne muscular dystrophy) as an example. Optimal handling during dissection, processing and sectioning is vital to avoid artifacts that can confound or prevent future analyses. Muscles carefully processed using this protocol are suitable for further evaluation using immunohistochemistry, immunofluorescence, special histochemical stains, and immuoblotting. © 2016 by John Wiley & Sons, Inc.

  5. Atlas-based automatic mouse brain image segmentation revisited: model complexity vs. image registration.

    PubMed

    Bai, Jordan; Trinh, Thi Lan Huong; Chuang, Kai-Hsiang; Qiu, Anqi

    2012-07-01

    Although many atlas-based segmentation methods have been developed and validated for the human brain, limited work has been done for the mouse brain. This paper investigated roles of image registration and segmentation model complexity in the mouse brain segmentation. We employed four segmentation models [single atlas, multiatlas, simultaneous truth and performance level estimation (STAPLE) and Markov random field (MRF) via four different image registration algorithms (affine, B-spline free-form deformation (FFD), Demons and large deformation diffeomorphic metric mapping (LDDMM)] for delineating 19 structures from in vivo magnetic resonance microscopy images. We validated their accuracies against manual segmentation. Our results revealed that LDDMM outperformed Demons, FFD and affine in any of the segmentation models. Under the same registration, increasing segmentation model complexity from single atlas to multiatlas, STAPLE or MRF significantly improved the segmentation accuracy. Interestingly, the multiatlas-based segmentation using nonlinear registrations (FFD, Demons and LDDMM) had similar performance to their STAPLE counterparts, while they both outperformed their MRF counterparts. Furthermore, when the single-atlas affine segmentation was used as reference, the improvement due to nonlinear registrations (FFD, Demons and LDDMM) in the single-atlas segmentation model was greater than that due to increasing model complexity (multiatlas, STAPLE and MRF affine segmentation). Hence, we concluded that image registration plays a more crucial role in the atlas-based automatic mouse brain segmentation as compared to model complexity. Multiple atlases with LDDMM can best improve the segmentation accuracy in the mouse brain among all segmentation models tested in this study.

  6. Estimating Lead (Pb) Bioavailability In A Mouse Model

    EPA Science Inventory

    Children are exposed to Pb through ingestion of Pb-contaminated soil. Soil Pb bioavailability is estimated using animal models or with chemically defined in vitro assays that measure bioaccessibility. However, bioavailability estimates in a large animal model (e.g., swine) can be...

  7. Evaluation of Listeria Monocytogenes Based Vaccines for HER-2/neu in Mouse Transgenic Models of Breast Cancer

    DTIC Science & Technology

    2007-09-01

    surrounding vessels in commonly studied mouse tumors. We have identified two autochthonous mouse mammary tumor models, MMTV-infected and MMTV-neu mice , with...Generate mammary specific inducible Tie2Ex mice a. Cross MMTV-rtTA mice with TRE-Tie2Ex mice (FVB and C3H strain). The Transgenic Mouse Facility...at Penn generated C3H/HeN TRE-Tie2Ex and FVB TRE-Tie2Ex transgenic mice using a TRE-Tie2Ex plasmid. Mouse lines that stably transmitted the

  8. Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology

    PubMed Central

    Szibor, Marten; Dhandapani, Praveen K.; Dufour, Eric; Holmström, Kira M.; Zhuang, Yuan; Salwig, Isabelle; Wittig, Ilka; Heidler, Juliana; Gizatullina, Zemfira; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě; Nandania, Jatin; Velagapudi, Vidya; Wietelmann, Astrid; Rustin, Pierre; Gellerich, Frank N.; Braun, Thomas

    2017-01-01

    ABSTRACT Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo. PMID:28067626

  9. Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology.

    PubMed

    Szibor, Marten; Dhandapani, Praveen K; Dufour, Eric; Holmström, Kira M; Zhuang, Yuan; Salwig, Isabelle; Wittig, Ilka; Heidler, Juliana; Gizatullina, Zemfira; Gainutdinov, Timur; Fuchs, Helmut; Gailus-Durner, Valérie; de Angelis, Martin Hrabě; Nandania, Jatin; Velagapudi, Vidya; Wietelmann, Astrid; Rustin, Pierre; Gellerich, Frank N; Jacobs, Howard T; Braun, Thomas

    2017-02-01

    Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOX(Rosa26) mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOX(Rosa26) mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.

  10. Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model

    PubMed Central

    Kazuki, Yasuhiro; Akita, Masaharu; Kobayashi, Kaoru; Osaki, Mitsuhiko; Satoh, Daisuke; Ohta, Ryo; Abe, Satoshi; Takehara, Shoko; Kazuki, Kanako; Yamazaki, Hiroshi; Kamataki, Tetsuya; Oshimura, Mitsuo

    2016-01-01

    Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans. PMID:26903378

  11. Dietary selenium deficiency exacerbates lipopolysaccharide-induced inflammatory response in mouse mastitis models.

    PubMed

    Wei, Zhengkai; Yao, Minjun; Li, Yimeng; He, Xuexiu; Yang, Zhengtao

    2014-12-01

    Selenium (Se) is an essential micronutrient that plays a critical role in anti-inflammatory processes and antioxidant defense system. In this study, we investigated the effects of dietary selenium deficiency on lipopolysaccharide (LPS)-induced mastitis in mouse models. Se content in the liver was assessed by fluorescent atomic absorption spectrometry. Glutathione peroxidase (GPx) activity in the blood, myeloperoxidase (MPO) activity, tumor necrosis actor alpha (TNF-α), and interleukin (IL)-1β in the supernatant of the mammary tissue were determined according to the corresponding kits. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions were evaluated by Western blotting. The results showed that the Se-deficient mouse model was successfully replicated, and selenium deficiency exacerbated mammary gland histopathology, increased the expressions of TNF-α and IL-1β, and facilitated the activation of iNOS and COX-2 in LPS-induced mouse mastitis. In conclusion, our studies demonstrated that selenium deficiency resulted in more severe inflammatory response in LPS-induced mouse mastitis.

  12. Thalidomide-induced limb abnormalities in a humanized CYP3A mouse model.

    PubMed

    Kazuki, Yasuhiro; Akita, Masaharu; Kobayashi, Kaoru; Osaki, Mitsuhiko; Satoh, Daisuke; Ohta, Ryo; Abe, Satoshi; Takehara, Shoko; Kazuki, Kanako; Yamazaki, Hiroshi; Kamataki, Tetsuya; Oshimura, Mitsuo

    2016-02-23

    Thalidomide is a teratogen in humans but not in rodents. It causes multiple birth defects including malformations of limbs, ears, and other organs. However, the species-specific mechanism of thalidomide teratogenicity is not completely understood. Reproduction of the human teratogenicity of thalidomide in rodents has previously failed because of the lack of a model reflecting human drug metabolism. In addition, because the maternal metabolic effect cannot be eliminated, the migration of unchanged thalidomide to embryos is suppressed, and the metabolic activation is insufficient to develop teratogenicity. Previously, we generated transchromosomic mice containing a human cytochrome P450 (CYP) 3A cluster in which the endogenous mouse Cyp3a genes were deleted. Here, we determined whether human CYP3A or mouse Cyp3a enzyme expression was related to the species difference in a whole embryo culture system using humanized CYP3A mouse embryos. Thalidomide-treated embryos with the human CYP3A gene cluster showed limb abnormalities, and human CYP3A was expressed in the placenta, suggesting that human CYP3A in the placenta may contribute to the teratogenicity of thalidomide. These data suggest that the humanized CYP3A mouse is a useful model to predict embryonic toxicity in humans.

  13. Mouse models of SMA: tools for disease characterization and therapeutic development.

    PubMed

    Bebee, Thomas W; Dominguez, Catherine E; Chandler, Dawn S

    2012-08-01

    Mouse models of human disease are an important tool for studying disease mechanism and manifestation in a way that is physiologically relevant. Spinal muscular atrophy (SMA) is a neurodegenerative disease that is caused by deletion or mutation of the survival motor neuron gene (SMN1). The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2. Correspondingly, a plethora of mouse models has been developed to mimic these different types of SMA. These models express a range of SMN protein levels and extensively cover the severe and mild types of SMA, with neurological and physiological manifestation of disease supporting the relevance of these models. The SMA models provide a strong background for studying SMA and have already shown to be useful in pre-clinical therapeutic studies. The purpose of this review is to succinctly summarize the genetic and disease characteristic of the SMA mouse models and to highlight their use for therapeutic testing.

  14. Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus.

    PubMed

    Mallipattu, Sandeep K; Gallagher, Emily J; LeRoith, Derek; Liu, Ruijie; Mehrotra, Anita; Horne, Sylvia J; Chuang, Peter Y; Yang, Vincent W; He, John C

    2014-05-01

    A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 diabetes mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, the MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia and thus are representative of nonobese human T2DM. We show that the MKR mice, when under stress (high-fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.

  15. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

    PubMed Central

    Anstee, Quentin M; Goldin, Robert D

    2006-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis. PMID:16436109

  16. Assessment of avoidance behaviors in mouse models of muscle pain

    PubMed Central

    Pratt, Dane; Fuchs, Perry N.; Sluka, Kathleen A.

    2014-01-01

    Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the cortex. Animal models typically use reflexive behaviors to test nociceptive responses; these are thought to reflect the sensory dimension of pain. While several behavioral tests are available for examining the affective dimension of pain it is unclear if these are appropriate in animal models of muscle pain. We therefore tested the utility of existing paradigms as well as new avoidance paradigms in animal models of muscle pain in mice. Specifically we used an escape-avoidance test to noxious mechanical stimuli, a learned avoidance test to noxious mechanical stimuli, and avoidance of physical activity. We used three animal models of muscle pain: carrageenan-induced inflammation, non-inflammatory muscle pain, and exercise-enhanced pain. In the carrageenan model of inflammation mice developed escape-avoidance behaviors to mechanical stimuli, learned avoidance to mechanical stimulation and avoidance of physical activity – these models are associated with unilateral hyperalgesia. When both muscles were inflamed, escape-avoidance behaviors did not develop suggesting equivalent bilateral pain-behaviors cannot be tested with an escape-avoidance test. In the non-inflammatory muscle pain model mice did not show significant changes in escape-avoidance behaviors or learned avoidance, but did avoid physical activity. In the exercise-enhanced pain model, there were no changes in escape avoidance, learned avoidance of noxious or physical activity In conclusion, we developed several testing protocols that assess supraspinal processing of pain-behaviors in models of muscle pain and that are most sensitive in animals with unilateral hyperalgesia. PMID:23747349

  17. A guide to histomorphological evaluation of intestinal inflammation in mouse models

    PubMed Central

    Erben, Ulrike; Loddenkemper, Christoph; Doerfel, Katja; Spieckermann, Simone; Haller, Dirk; Heimesaat, Markus M; Zeitz, Martin; Siegmund, Britta; Kühl, Anja A

    2014-01-01

    Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating inter-study comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease. PMID:25197329

  18. A guide to histomorphological evaluation of intestinal inflammation in mouse models.

    PubMed

    Erben, Ulrike; Loddenkemper, Christoph; Doerfel, Katja; Spieckermann, Simone; Haller, Dirk; Heimesaat, Markus M; Zeitz, Martin; Siegmund, Britta; Kühl, Anja A

    2014-01-01

    Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating inter-study comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease.

  19. Determination of human transferrin concentrations in mouse models of neisserial infection.

    PubMed

    Perera, Yasser; Cobas, Karen; Garrido, Yainelis; Nazabal, Consuelo; Brown, Enma; Pajon, Rolando

    2006-04-20

    Transferrin constitutes the major protein involved in the transport of iron from the sites of absorption to the sites of storage and utilization. Despite the high affinity of transferrin for iron, most bacterial pathogens, such as the human restricted Neisseria meningitidis, have developed iron acquisition mechanisms. Several animal models of bacterial infection that include the exogenous supply of human transferrin have been implemented, and tests using transgenic mouse models are underway. Here we describe an ELISA sandwich procedure based on two monoclonal antibodies with negligible cross-reactivity to murine transferrin, to estimate human transferrin concentrations in mouse sera. The assay can detect as little as 10 ng/ml of human transferrin with coefficients of variation ranging from 1.6% to 4.4% (intra-assay) and 3.8% to 5% (inter-assay). The recovery values range from 90% to 110% in the assay working range (25-400 ng/ml). Human transferrin concentrations estimated in sera from 41 human transferrin transgenic mice ranged from 2 to 14 microg/ml. Further estimations of human transferrin levels in mouse sera of a previously described mouse model of N. meningitidis were also carried out. The intraperitoneal injection of 8 mg of human transferrin achieved a sustained value of human transferrin in mouse sera in the range of 1-2mg/ml over the first 24h, indicating that bacteria reaching the blood stream during this time would be exposed to levels of hTf found in normal human serum.

  20. The circling mutant Pcdh15roda is a new mouse model for hearing loss.

    PubMed

    Torres, Adriana Amorim; Rzadzinska, Agnieszka K; Ribeiro, Andrea Frozino; Silva, Daniel Almeida da Silva E; Guénet, Jean-Louis; Massironi, Sílvia Maria Gomes; Godard, Ana Lúcia Brunialti

    2013-01-01

    Mouse mutagenesis is a key tool for studying gene function and several mutant alleles have been described and constitute mouse models for human hereditary diseases. Genetic hearing loss represents over 50% of all hearing loss cases in children and, due to the heterogeneity of the disorder, there is still a demand for the isolation and characterization of new genes and alleles. Here we report phenotypic and molecular characterization of a new mouse model for hereditary hearing loss. The mutant rodador, isolated by Massironi and colleagues in 2006, presents an autosomal recessive disorder characterized by deafness and balance dysfunction associated with abnormal stereocilia in the inner ear. The mutation was mapped to mouse chromosome 10, and characterization of the gene Pcdh15 revealed an AT-to-GC transition in intron 23 of mutant animals. The alteration led to the switch of a dinucleotide ApA for ApG, creating a novel intronic acceptor splice site, which leads to incorporation of eight intronic bases into the processed mRNA and alteration of the downstream reading frame. In silico analysis indicated that the mutated protein is truncated and lacks two cadherin domains, and the transmembrane and cytoplasmic domains. Real Time PCR analyses revealed a significantly reduced Pcdh15 mRNA level in the brain of mutant mice, which might be due to the mechanism of non-sense mediated decay. In man, mutations in the orthologue PCDH15 cause non-syndromic deafness and Usher Syndrome Type 1F, a genetic disorder characterized by hearing loss and retinitis pigmentosa. Rodador mouse constitutes a new model for studying deafness in these conditions and may help in the comprehension of the pathogeneses of the disease, as well as of the mechanisms involved in the morphogenesis and function of inner ear stereocilia. This is a new ENU-induced allele and the first isolated in a BALB/c background.

  1. Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology.

    PubMed

    Ahmed, Rebekah M; Irish, Muireann; van Eersel, Janet; Ittner, Arne; Ke, Yazi D; Volkerling, Alexander; van der Hoven, Julia; Tanaka, Kimi; Karl, Tim; Kassiou, Michael; Kril, Jillian J; Piguet, Olivier; Götz, Jürgen; Kiernan, Matthew C; Halliday, Glenda M; Hodges, John R; Ittner, Lars M

    2017-03-01

    Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.

  2. A model for gas and nutrient exchange in the chorionic vasculature system of the mouse placenta

    NASA Astrophysics Data System (ADS)

    Mirbod, Parisa; Sled, John

    2015-11-01

    The aim of this study is to develop an analytical model for the oxygen and nutrient transport from the umbilical cord to the small villous capillaries. The nutrient and carbon dioxide removal from the fetal cotyledons in the mouse placental system has also been considered. This model describes the mass transfer between the fetal and the maternal red blood cells in the chorionic arterial vasculature system. The model reveals the detail fetal vasculature system and its geometry and the precise mechanisms of mass transfer through the placenta. The dimensions of the villous capillaries, the total length of the villous trees, the total villi surface area, and the total resistance to mass transport in the fetal villous trees has also been defined. This is the first effort to explain the reason why there are at least 7 lobules in the mouse placenta from the fluid dynamics point of view.

  3. Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models

    PubMed Central

    Uchida, Aki; Zigman, Jeffrey M.; Perelló, Mario

    2013-01-01

    Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin's effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models. These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue receptor (GHSR)] or the enzyme that post-translationally modifies ghrelin [ghrelin O-acyltransferase (GOAT)]. In addition, a GHSR-null mouse model in which GHSR transcription is globally blocked but can be cell-specifically reactivated in a Cre recombinase-mediated fashion has been generated. Here, we summarize findings obtained with these genetically manipulated mice, with the aim to highlight the significance of the ghrelin system in the regulation of both homeostatic and hedonic eating, including that occurring in the setting of chronic psychosocial stress. PMID:23882175

  4. Bezafibrate improves mitochondrial function in the CNS of a mouse model of mitochondrial encephalopathy

    PubMed Central

    Noe, Natalie; Dillon, Lloye; Lellek, Veronika; Diaz, Francisca; Hida, Aline; Moraes, Carlos T.; Wenz, Tina

    2013-01-01

    Mitochondrial dysfunction frequently affects the central nervous system. Here, we investigated the effect of bezafibrate treatment on neuronal mitochondrial function and its impact on the progression of a mitochondrial encephalopathy. We used a murine model with a forebrain-specific cytochrome c oxidase deficiency caused by conditional deletion of the COX10 gene. In this mouse model, bezafibrate-administration improved the phenotype of the mice associated with an increase in mitochondrial proteins and mitochondrial ATP generating capacity. Bezafibrate-treatment also attenuated astrogliosis and decreased the level of inflammatory markers in the affected tissues. Overall, bezafibrate had a neuroprotective effect in this mouse model of mitochondrial encephalopathy. These findings imply that bezafibrate might be a promising therapeutic agent for the treatment of neurodegenerative disease associated with mitochondrial dysfunction. PMID:23261681

  5. Mathematical model of mouse embryonic cardiomyocyte excitation-contraction coupling.

    PubMed

    Korhonen, Topi; Rapila, Risto; Tavi, Pasi

    2008-10-01

    Excitation-contraction (E-C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca(2+) signals and contractions (E-C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca(2+) releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na(+)/Ca(2+) exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca(2+) intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E-C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca(2+) dynamics and oscillatory SR Ca(2+) handling. The model reproduces faithfully the experimentally observed fundamental features of both E-C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca(2+) buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes.

  6. Mathematical Model of Mouse Embryonic Cardiomyocyte Excitation–Contraction Coupling

    PubMed Central

    Korhonen, Topi; Rapila, Risto; Tavi, Pasi

    2008-01-01

    Excitation–contraction (E–C) coupling is the mechanism that connects the electrical excitation with cardiomyocyte contraction. Embryonic cardiomyocytes are not only capable of generating action potential (AP)-induced Ca2+ signals and contractions (E–C coupling), but they also can induce spontaneous pacemaking activity. The spontaneous activity originates from spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR), which trigger APs via the Na+/Ca2+ exchanger (NCX). In the AP-driven mode, an external stimulus triggers an AP and activates voltage-activated Ca2+ intrusion to the cell. These complex and unique features of the embryonic cardiomyocyte pacemaking and E–C coupling have never been assessed with mathematical modeling. Here, we suggest a novel mathematical model explaining how both of these mechanisms can coexist in the same embryonic cardiomyocytes. In addition to experimentally characterized ion currents, the model includes novel heterogeneous cytosolic Ca2+ dynamics and oscillatory SR Ca2+ handling. The model reproduces faithfully the experimentally observed fundamental features of both E–C coupling and pacemaking. We further validate our model by simulating the effect of genetic modifications on the hyperpolarization-activated current, NCX, and the SR Ca2+ buffer protein calreticulin. In these simulations, the model produces a similar functional alteration to that observed previously in the genetically engineered mice, and thus provides mechanistic explanations for the cardiac phenotypes of these animals. In general, this study presents the first model explaining the underlying cellular mechanism for the origin and the regulation of the heartbeat in early embryonic cardiomyocytes. PMID:18794378

  7. PRIORITIZING THE DEVELOPMENT OF MOUSE MODELS FOR CHILDHOOD BRAIN DISORDERS

    PubMed Central

    Ogden, Kevin K.; Ozkan, Emin D.; Rumbaugh, Gavin

    2015-01-01

    Mutations in hundreds of genes contribute to cognitive and behavioral dysfunction associated with developmental brain disorders (DBDs). Due to the sheer number of risk factors available for study combined with the cost of developing new animal models, it remains an open question how genes should be prioritized for in-depth neurobiological investigations. Recent reviews have argued that priority should be given to frequently mutated genes commonly found in sporadic DBD patients. Intrigued by this idea, we explored to what extent “high priority” risk factors have been studied in animals in an effort to assess their potential for generating valuable preclinical models capable of advancing the neurobiological understanding of DBDs. We found that in-depth whole animal studies are lacking for many high priority genes, with relatively few neurobiological studies performed in construct valid animal models aimed at understanding the pathological substrates associated with disease phenotypes. However, some high priority risk factors have been extensively studied in animal models and they have generated novel insights into DBD patho-neurobiology while also advancing early pre-clinical therapeutic treatment strategies. We suggest that prioritizing model development toward genes frequently mutated in non-specific DBD populations will accelerate the understanding of DBD patho-neurobiology and drive novel therapeutic strategies. PMID:26231830

  8. Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma

    PubMed Central

    Chiu, Amy P; Tschida, Barbara R; Lo, Lilian H; Moriarity, Branden S; Rowlands, Dewi K; Largaespada, David A; Keng, Vincent W

    2015-01-01

    The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV-associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia. PMID:26576100

  9. The primate autoimmune encephalomyelitis model; a bridge between mouse and man

    PubMed Central

    ‘t Hart, Bert A; van Kooyk, Yvette; Geurts, Jeroen J G; Gran, Bruno

    2015-01-01

    Introduction Multiple sclerosis (MS) is an enigmatic autoimmune-driven inflammatory/demyelinating disease of the human central nervous system (CNS), affecting brain, spinal cord, and optic nerves. The cause of the disease is not known and the number of effective treatments is limited. Despite some clear successes, translation of immunological discoveries in the mouse experimental autoimmune encephalomyelitis (EAE) model into effective therapies for MS patients has been difficult. This translation gap between MS and its elected EAE animal model reflects the phylogenetic distance between humans and their experimental counterpart, the inbred/specific pathogen free (SPF) laboratory mouse. Objective Here, we discuss that important new insights can be obtained into the mechanistic basis of the therapy paradox from the study of nonhuman primate EAE (NHP-EAE) models, the well-validated EAE model in common marmosets (Callithrix jacchus) in particular. Interpretation Data presented in this review demonstrate that due to a considerable immunological and pathological overlap with mouse EAE on one side and MS on the other, the NHP EAE model can help us bridge the translation gap. PMID:26000330

  10. Mouse models of neurological disorders--a comparison of heritable and acquired traits.

    PubMed

    Harper, Alex

    2010-10-01

    Human neurological disorders include a wide range of illnesses which have a disproportionately high prevalence in the increasingly populous geriatric community. Any research effort directed at discovering the aetiology of neurological disease is greatly enhanced with in vivo models of the disease of interest. Scientific research incorporating the use of mice has advanced rapidly in the last three decades. Relatively simple to breed, maintain and train, mice have many advantages over other species for use in research. More than a century of selective breeding has provided investigators with a rich gene pool and sub-strain diversity from which to choose for their research. Thus the dramatic increase in genetic screening and gene engineering that has occurred in research in recent decades has enabled the generation of a multitude of mouse models. This review discusses the relative utility of mouse models in which a heritable or non-heritable (acquired) manipulation has been used to model a specified trait of a human neurological disorder. The techniques used in deriving useful genetic alterations or modifications and in generating acquired mouse models are outlined with examples of each provided.

  11. A Dual Reporter Mouse Model of the Human β-Globin Locus: Applications and Limitations

    PubMed Central

    Papadopoulos, Petros; Gutiérrez, Laura; van der Linden, Reinier; Kong-A-San, John; Maas, Alex; Drabek, Dubravka; Patrinos, George P.; Philipsen, Sjaak; Grosveld, Frank

    2012-01-01

    The human β-globin locus contains the β-like globin genes (i.e. fetal γ-globin and adult β-globin), which heterotetramerize with α-globin subunits to form fetal or adult hemoglobin. Thalassemia is one of the commonest inherited disorders in the world, which results in quantitative defects of the globins, based on a number of genome variations found in the globin gene clusters. Hereditary persistence of fetal hemoglobin (HPFH) also caused by similar types of genomic alterations can compensate for the loss of adult hemoglobin. Understanding the regulation of the human γ-globin gene expression is a challenge for the treatment of thalassemia. A mouse model that facilitates high-throughput assays would simplify such studies. We have generated a transgenic dual reporter mouse model by tagging the γ- and β-globin genes with GFP and DsRed fluorescent proteins respectively in the endogenous human β-globin locus. Erythroid cell lines derived from this mouse model were tested for their capacity to reactivate the γ-globin gene. Here, we discuss the applications and limitations of this fluorescent reporter model to study the genetic basis of red blood cell disorders and the potential use of such model systems in high-throughput screens for hemoglobinopathies therapeutics. PMID:23272095

  12. The Construction of Transgenic and Gene Knockout/Knockin Mouse Models of Human Disease

    PubMed Central

    Doyle, Alfred; McGarry, Michael P.; Lee, Nancy A.; Lee, James J.

    2012-01-01

    The genetic and physiological similarities between mice and humans have focused considerable attention on rodents as potential models of human health and disease. Together with the wealth of resources, knowledge, and technologies surrounding the mouse as a model system, these similarities have propelled this species to the forefront of biomedical research. The advent of genomic manipulation has quickly led to the creation and use of genetically engineered mice as powerful tools for cutting edge studies of human disease research, including the discovery, refinement, and utility of many currently available therapeutic regimes. In particular, the creation of genetically modified mice as models of human disease has remarkably changed our ability to understand the molecular mechanisms and cellular pathways underlying disease states. Moreover, the mouse models resulting from gene transfer technologies have been important components correlating an individual’s gene expression profile to the development of disease pathologies. The objective of this review is to provide physician-scientists with an expansive historical and logistical overview of the creation of mouse models of human disease through gene transfer technologies. Our expectation is that this will facilitate on-going disease research studies and may initiate new areas of translational research leading to enhanced patient care. PMID:21800101

  13. Distinctive serum miRNA profile in mouse models of striated muscular pathologies.

    PubMed

    Vignier, Nicolas; Amor, Fatima; Fogel, Paul; Duvallet, Angélique; Poupiot, Jérôme; Charrier, Sabine; Arock, Michel; Montus, Marie; Nelson, Isabelle; Richard, Isabelle; Carrier, Lucie; Servais, Laurent; Voit, Thomas; Bonne, Gisèle; Israeli, David

    2013-01-01

    Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs) as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), Emery-Dreifuss muscular dystrophy (EDMD) and hypertrophic cardiomyopathy (HCM). Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD.

  14. Clinical applications of mouse models for breast cancer engaging HER2/neu

    PubMed Central

    Fry, Elizabeth A.; Taneja, Pankaj; Inoue, Kazushi

    2016-01-01

    Human c-ErbB2 (HER2) has long been used as a marker of breast cancer (BC) for sub-categorization for the prediction of prognosis, and determination of therapeutic strategies. HER2 overexpressing BCs are more invasive/metastatic; but patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors, at least at early stages. To date, numerous mouse models that faithfully reproduce HER2(+) BCs have been created in mice. We recently reviewed different mouse models of BC overexpressing wild type or mutant neu driven by MMTV, neu, or doxycycline-inducible promoters. These mice have been used to demonstrate the histopathology, oncogenic signaling pathways initiated by aberrant overexpression of HER2 in the mammary epithelium, and interaction between oncogenes and tumor suppressor genes at molecular levels. In this review, we focus on their clinical applications. They can be used to test the efficacy of HER(2) inhibitors before starting clinical trials, characterize the tumor-initiating cells that could be the cause of relapse after therapy as well as to analyze the molecular mechanisms of therapeutic resistance targeting HER2. MMTV-human ErbB2 (HER2) mouse models have recently been established since the monoclonal antibody to HER2 (trastuzumab; Herceptin®) does not recognize the rat neu protein. It has been reported that early intervention with HER2 monoclonal antibody would be beneficial for preventing mammary carcinogenesis. MDA-7/IL-24 as well as naturally-occurring chemicals have also been tested using MMTV-neu models. Recent studies have shown that MMTV-neu models are useful to develop vaccines to HER2 for immunotherapy. The mouse models employing HER2/neu will be essential for future antibody or drug screenings to overcome resistance to trastuzumab or HER(2)-specific tyrosine kinase inhibitors. PMID:28133539

  15. Mouse models of advanced spontaneous metastasis for experimental therapeutics

    PubMed Central

    Francia, Giulio; Cruz-Munoz, William; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2015-01-01

    An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. PMID:21258397

  16. The Monoiodoacetate Model of Osteoarthritis Pain in the Mouse

    PubMed Central

    Pitcher, Thomas; Sousa-Valente, João; Malcangio, Marzia

    2016-01-01

    A major symptom of patients with osteoarthritis (OA) is pain that is triggered by peripheral as well as central changes within the pain pathways. The current treatments for OA pain such as NSAIDS or opiates are neither sufficiently effective nor devoid of detrimental side effects. Animal models of OA are being developed to improve our understanding of OA-related pain mechanisms and define novel pharmacological targets for therapy. Currently available models of OA in rodents include surgical and chemical interventions into one knee joint. The monoiodoacetate (MIA) model has become a standard for modelling joint disruption in OA in both rats and mice. The model, which is easier to perform in the rat, involves injection of MIA into a knee joint that induces rapid pain-like responses in the ipsilateral limb, the level of which can be controlled by injection of different doses. Intra-articular injection of MIA disrupts chondrocyte glycolysis by inhibiting glyceraldehyde-3-phosphatase dehydrogenase and results in chondrocyte death, neovascularization, subchondral bone necrosis and collapse, as well as inflammation. The morphological changes of the articular cartilage and bone disruption are reflective of some aspects of patient pathology. Along with joint damage, MIA injection induces referred mechanical sensitivity in the ipsilateral hind paw and weight bearing deficits that are measurable and quantifiable. These behavioral changes resemble some of the symptoms reported by the patient population, thereby validating the MIA injection in the knee as a useful and relevant pre-clinical model of OA pain. The aim of this article is to describe the methodology of intra-articular injections of MIA and the behavioral recordings of the associated development of hypersensitivity with a mind to highlight the necessary steps to give consistent and reliable recordings. PMID:27214709

  17. Fulminant liver failure model with hepatic encephalopathy in the mouse

    PubMed Central

    Hori, Tomohide; Chen, Feng; Baine, Ann-Marie T.; Gardner, Lindsay B.; Nguyen, Justin H.

    2011-01-01

    Aim To develop a reliable murine model for fulminant liver failure (FLF). Material and Methods We treated three groups of male C57BL/6 mice:as controls, with azoxymethane (AOM), and with galactosamine (Gal) and tumor necrosis factor-alpha (TNFα). Effects of body temperature (BT) control on survival, in all three groups were investigated. Using BT control, survival, histopathological findings and biochemical/coagulation profiles were compared between the experimental groups. Effects of hydration on international normalized ratios of prothrombin time (PT-INR) were also checked. Dose-dependent survival curves were made for both experimental groups. Neurological behaviors were assessed using a coma scale. Results No unexpected BT effects were seen in the control group. The AOM group, but not the Gal+TNFα group, showed significant differences in survival curves between those with and without BT care. Histopathological assessment showed consistent FLF findings in both experimental groups with BT care. Between the experimental groups, there were significant differences in aspartate aminotransferase levels and PT-INR; and significant differences in PT-INRs between sufficiently- and insufficiently-hydrated groups. There were significant differences between FLF models, in the duration of each coma stage, with significant differences in stages 1 and 3 as percentages of the diseased state (stages 1-4). The two FLF models with BT care showed different survival curves in the dose-dependent survival study. Conclusion Azoxymethane can provide a good FLF model, but requires a specialized environment and careful BT control. Other FLF models may also be useful, depending on research purpose. Thoughtful attention to caregiving and close observation are indispensable for successful FLF models. PMID:24713795

  18. Quantification of Lung Metastases from In Vivo Mouse Models.

    PubMed

    Chang, Joan; Erler, Janine T

    2016-01-01

    Cancer research has made significant progress in terms of understanding and targeting primary tumors; however, the challenge remains for the successful treatment of metastatic cancers. This highlights the importance to use in vivo models to study the metastatic process, as well as for preclinical testing of compounds that could inhibit metastasis. As a result, proper quantification of metastases from in vivo models is of the utmost significance. Here, we provide a detailed protocol for collecting and handling lung tissues from mice, and guidance for subsequent analysis of metastases, as well as interpretation of data.

  19. SIRT1 metabolic actions: Integrating recent advances from mouse models.

    PubMed

    Boutant, Marie; Cantó, Carles

    2014-02-01

    SIRT1 has attracted a lot of interest since it was discovered as a mammalian homolog of Sir2, a protein that influences longevity in yeast. Intensive early research suggested a key role of SIRT1 in mammalian development, metabolic flexibility and oxidative metabolism. However, it is the growing body of transgenic models that are allowing us to clearly define the true range of SIRT1 actions. In this review we aim to summarize the most recent lessons that transgenic animal models have taught us about the role of SIRT1 in mammalian metabolic homeostasis and lifespan.

  20. Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome-wide association and polygenic scoring study

    PubMed Central

    Mullins, Niamh; Perroud, Nader; Uher, Rudolf; Butler, Amy W; Cohen-Woods, Sarah; Rivera, Margarita; Malki, Karim; Euesden, Jack; Power, Robert A; Tansey, Katherine E; Jones, Lisa; Jones, Ian; Craddock, Nick; Owen, Michael J; Korszun, Ania; Gill, Michael; Mors, Ole; Preisig, Martin; Maier, Wolfgang; Rietschel, Marcella; Rice, John P; Müller-Myhsok, Bertram; Binder, Elisabeth B; Lucae, Susanne; Ising, Marcus; Craig, Ian W; Farmer, Anne E; McGuffin, Peter; Breen, Gerome; Lewis, Cathryn M

    2014-01-01

    Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc. PMID:24964207

  1. A Novel Mouse Model of Penetrating Brain Injury

    PubMed Central

    Cernak, Ibolja; Wing, Ian D.; Davidsson, Johan; Plantman, Stefan

    2014-01-01

    Penetrating traumatic brain injury (pTBI) has been difficult to model in small laboratory animals, such as rats or mice. Previously, we have established a non-fatal, rat model for pTBI using a modified air-rifle that accelerates a pellet, which hits a small probe that then penetrates the experimental animal’s brain. Knockout and transgenic strains of mice offer attractive tools to study biological reactions induced by TBI. Hence, in the present study, we adapted and modified our model to be used with mice. The technical characterization of the impact device included depth and speed of impact, as well as dimensions of the temporary cavity formed in a brain surrogate material after impact. Biologically, we have focused on three distinct levels of severity (mild, moderate, and severe), and characterized the acute phase response to injury in terms of tissue destruction, neural degeneration, and gliosis. Functional outcome was assessed by measuring bodyweight and motor performance on rotarod. The results showed that this model is capable of reproducing major morphological and neurological changes of pTBI; as such, we recommend its utilization in research studies aiming to unravel the biological events underlying injury and regeneration after pTBI. PMID:25374559

  2. Photoimmunotherapy of Gastric Cancer Peritoneal Carcinomatosis in a Mouse Model

    PubMed Central

    Sato, Kazuhide; Choyke, Peter L.; Kobayashi, Hisataka

    2014-01-01

    Photoimmunotherapy (PIT) is a new cancer treatment that combines the specificity of antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. We performed PIT in a model of disseminated gastric cancer peritoneal carcinomatosis and monitored efficacy with in vivo GFP fluorescence imaging. In vitro and in vivo experiments were conducted with a HER2-expressing, GFP-expressing, gastric cancer cell line (N87-GFP). A conjugate comprised of a photosensitizer, IR-700, conjugated to trastuzumab (tra-IR700), followed by NIR light was used for PIT. In vitro PIT was evaluated by measuring cytotoxicity with dead staining and a decrease in GFP fluorescence. In vivo PIT was evaluated in a disseminated peritoneal carcinomatosis model and a flank xenograft using tumor volume measurements and GFP fluorescence intensity. In vivo anti-tumor effects of PIT were confirmed by significant reductions in tumor volume (at day 15, p<0.0001 vs. control) and GFP fluorescence intensity (flank model: at day 3, PIT treated vs. control p<0.01 and peritoneal disseminated model: at day 3 PIT treated vs. control, p<0.05). Cytotoxic effects in vitro were shown to be dependent on the light dose and caused necrotic cell rupture leading to GFP release and a decrease in fluorescence intensity in vitro. Thus, loss of GFP fluorescence served as a useful biomarker of cell necrosis after PIT. PMID:25401794

  3. A mouse model of human repetitive mild traumatic brain injury

    PubMed Central

    Kane, Michael J.; Pérez, Mariana Angoa; Briggs, Denise I.; Viano, David C.; Kreipke, Christian W.; Kuhn, Donald M.

    2011-01-01

    A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 minutes. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel. PMID:21930157

  4. A mouse model of human repetitive mild traumatic brain injury.

    PubMed

    Kane, Michael J; Angoa-Pérez, Mariana; Briggs, Denise I; Viano, David C; Kreipke, Christian W; Kuhn, Donald M

    2012-01-15

    A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 min. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel.

  5. SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice.

    PubMed Central

    Slaga, T J

    1986-01-01

    The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters. PMID:3096709

  6. Abnormalities in the tricarboxylic Acid cycle in Huntington disease and in a Huntington disease mouse model.

    PubMed

    Naseri, Nima N; Xu, Hui; Bonica, Joseph; Vonsattel, Jean Paul G; Cortes, Etty P; Park, Larry C; Arjomand, Jamshid; Gibson, Gary E

    2015-06-01

    Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (-50% to 90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the human HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%) suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients.

  7. Abnormalities in the Tricarboxylic Acid Cycle in Huntington Disease and in a Huntington Disease Mouse Model

    PubMed Central

    Naseri, Nima N.; Xu, Hui; Bonica, Joseph; Vonsattel, Jean Paul G.; Cortes, Etty P.; Park, Larry C.; Arjomand, Jamshid; Gibson, Gary E.

    2015-01-01

    Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (−50%–90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%), suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients. PMID:25978848

  8. Adaptation of influenza A(H1N1)pdm09 virus in experimental mouse models.

    PubMed

    Prokopyeva, E A; Sobolev, I A; Prokopyev, M V; Shestopalov, A M

    2016-04-01

    In the present study, three mouse-adapted variants of influenza A(H1N1)pdm09 virus were obtained by lung-to-lung passages of BALB/c, C57BL/6z and CD1 mice. The significantly increased virulence and pathogenicity of all of the mouse-adapted variants induced 100% mortality in the adapted mice. Genetic analysis indicated that the increased virulence of all of the mouse-adapted variants reflected the incremental acquisition of several mutations in PB2, PB1, HA, NP, NA, and NS2 proteins. Identical amino acid substitutions were also detected in all of the mouse-adapted variants of A(H1N1)pdm09 virus, including PB2 (K251R), PB1 (V652A), NP (I353V), NA (I106V, N248D) and NS1 (G159E). Apparently, influenza A(H1N1)pdm09 virus easily adapted to the host after serial passages in the lungs, inducing 100% lethality in the last experimental group. However, cross-challenge revealed that not all adapted variants are pathogenic for different laboratory mice. Such important results should be considered when using the influenza mice model.

  9. SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice

    SciTech Connect

    Slaga, T.J.

    1986-09-01

    The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters.

  10. A mighty mouse: building a better model of multiple sclerosis

    PubMed Central

    Ransohoff, Richard M.

    2006-01-01

    The 2 cardinal cell populations mediating adaptive immunity are T and B lymphocytes. These cells play important but poorly understood roles in the immunopathological demyelinating disease multiple sclerosis (MS) and in a widely used animal model of human MS known as EAE. In the current issue of the JCI, 2 research teams report their parallel studies of double-transgenic mice expressing T and B cell receptors that recognize the same myelin protein (see the related articles beginning on pages 2385 and 2393). More than half of the double-transgenic mice spontaneously developed autoimmune demyelination in their spinal cords and optic nerves, exhibiting pathologies reminiscent of human MS. The studies describe an important new model for MS research. PMID:16955130

  11. Transgenic mouse model for imaging of interleukin-1β-related inflammation in vivo

    PubMed Central

    Iwawaki, Takao; Akai, Ryoko; Oikawa, Daisuke; Toyoshima, Takae; Yoshino, Mayuko; Suzuki, Mitsumi; Takeda, Naoki; Ishikawa, Tomo-o; Kataoka, Yosky; Yamamura, Ken-ichi

    2015-01-01

    Inflammation is a biological response associated with symptoms of various diseases, and its study is important in gaining an understan