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Pathol Res Pract. 2012 Jul 15;208(7):377-81. doi: 10.1016/j.prp.2012.04.006. Epub 2012 Jun 8.
The influence of physical activity in the progression of experimental lung cancer in mice
Renato Batista Paceli 1, Rodrigo Nunes Cal, Carlos Henrique Ferreira dos Santos, José Antonio Cordeiro, Cassiano Merussi Neiva, Kazuo Kawano Nagamine, Patrícia Maluf Cury
- PMID: 22683274
- DOI: 10.1016/j.prp.2012.04.006
Impact_Fator-wise_Top100Science_Journals
GRUPO_AF1 – GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 1 – GROUP AFAN1 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO_AF2 – GROUP AFA2 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 2 – GROUP AFAN 2 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Slides – mestrado – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
CARCINÓGENO DMBA EM MODELOS EXPERIMENTAIS
DMBA CARCINOGEN IN EXPERIMENTAL MODELS
Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
https://pubmed.ncbi.nlm.nih.gov/22683274/
Abstract
Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.
Copyright © 2012 Elsevier GmbH. All rights reserved.
´´A dissertation is a subject you chose for yourself. The first usage of the word in the English language in 1651 also gives a useful starting definition: “an extended written treatment of a subject”. Another useful clue is found in the Latin origin of the word – dissertation comes from a Latin word ‘dissertare’ = ‘to debate’. ´´ @

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- PiggyBAC TransgenicsGet your single copy transgenic mice in as little as 3 months. Read More ›
- Thankful for You – New Testimonials for Cyagen’s Animal Serv…
With the upcoming Thanksgiving Holiday in the US – Cyagen would like to thank you for everything you do to make the world a better place. Read More › - Differentiating the Biological Functions of Nestin with Tran…
Since the identification of the intermediate filament (IF), nestin, it has been used as a marker for Neural Stem Cells (NSCs) and commonly considered as a key component … Read More › - KO-First: A Tool for Studying Gene Function Across the Mamma…
Since the early 2000s, large-scale knockout consortia have been established with the goal of generating a complete resource of reporter-tagged null mutations in C57BL/6 mouse ES cells. Herein, … Read More › - CRISPR-Cas9: How the Patent Dispute has Transformed Science …
As CRISPR-based innovations begin to move into clinical testing and the dispute over core patents continues worldwide, CRISPR-Cas9 gene editing has been under increased scrutiny in both commercial … Read More › - RPS23RG1-mediated Stabilization of Synaptic Function Rescues…
Synaptic impairment is known to be a prerequisite to the cognitive deficiencies exhibited in Alzheimer’s Disease (AD), so investigating the mechanisms which Read More › - Advancing the Study of Cardiac Chamber Specification During …
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Save up to 25%on all custom animal modelsTurboKnockout® MicecKO | cKI | LFKI | HumanizedPiggyBac TransgenicRats | Mice | Mouse EmbryosDesign Your ModelFREE Projects Strategies InstantlyStem Cells and ProductsHigh qualityPromotions
- Discount of the Decade EventOur Discount of the Decade Event can help you extend your research with big savings for custom model generation projects. If your research would benefit from generation of … Read More ›
- Grant Application Support LetterIf you are considering applying for a grant, reviewers will seek to understand the strategies used in generating any research models for your proposal. Cyagen’s model generation experts … Read More ›
- Stem Cells and Media – High Quality & ReliableCyagen offers high quality and reliable research-use cell products to researchers around the world. Until now, Cyagen’s products have been referenced in over 1,200 customer publications, cited by … Read More ›
- Cryopreservation & BreedingTake advantage of our Cryopreservation and Breeding services to save time, space and money. Read More ›
- ROSA26 Large Fragment KnockinWith highly competitive pricing, backed by a 100% money-back guarantee. Read More ›
- PiggyBAC TransgenicsGet your single copy transgenic mice in as little as 3 months. Read More ›
- Thankful for You – New Testimonials for Cyagen’s Animal Serv…
With the upcoming Thanksgiving Holiday in the US – Cyagen would like to thank you for everything you do to make the world a better place. Read More › - Differentiating the Biological Functions of Nestin with Tran…
Since the identification of the intermediate filament (IF), nestin, it has been used as a marker for Neural Stem Cells (NSCs) and commonly considered as a key component … Read More › - KO-First: A Tool for Studying Gene Function Across the Mamma…
Since the early 2000s, large-scale knockout consortia have been established with the goal of generating a complete resource of reporter-tagged null mutations in C57BL/6 mouse ES cells. Herein, … Read More › - CRISPR-Cas9: How the Patent Dispute has Transformed Science …
As CRISPR-based innovations begin to move into clinical testing and the dispute over core patents continues worldwide, CRISPR-Cas9 gene editing has been under increased scrutiny in both commercial … Read More › - RPS23RG1-mediated Stabilization of Synaptic Function Rescues…
Synaptic impairment is known to be a prerequisite to the cognitive deficiencies exhibited in Alzheimer’s Disease (AD), so investigating the mechanisms which Read More › - Advancing the Study of Cardiac Chamber Specification During …
Nppa (natriuretic peptide A) is a cardiac hormone that dynamically changes its spatiotemporal expression during heart development. Read More ›
- Kartogenin hydrolysis product 4-aminobiphenyl distributes to cartilage and mediates cartilage regeneration.Theranostics 9: 7108-7121 (2019)
- CRYAB promotes osteogenic differentiation of human bone marrow stem cells via stabilizing β-catenin and promot…Cell Proliferation PMID: 31638302 (2019)
- Transforming Growth Factor-β3/Chitosan Sponge (TGF-β3/CS) Facilitates Osteogenic Differentiation of Human Peri…International Journal Of Molecular Sciences 9: 20 (2019)
- Periosteal matrix-derived hydrogel promotes bone repair through an early immune regulation coupled with enhanc…Biomaterials 227: 119552 (2019)
- Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology.Cells 8. pii: E1359 (2019)
- Synergistic effects of adipose-derived stem cells combined with decellularized myocardial matrix on the treatm…Life SciencesLIFE SCIENCES 12:116891 (2019)
Find publications relevant to your research:Citation SearchCyagen US Inc.
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- 408-969-0336
- animal-service@cyagen.com (Animal Model Services)cell-service@cyagen.com (Cell Products and Services)
- · Stem Cells
- · Fluorescent-Labeled Cells
- · Primary Cells
- · Stem Cell Culture Media
- · Stem Cell Differentiation Media
- · Cell Cryopreservation Media
- · Primary Cell Culture Media
Copyright © 2019 Cyagen Biosciences. All rights reserved.
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Mouse Model
Mouse models can be considered as the starting point for investigating a certain basic principle, without having an aim to translate it into humans, just like other non-human models such as yeast, fruit fly or zebrafish, depending on the nature of the question in study: for example, studying the mechanism of heat shock proteins in the antigen presentation process or understanding the survival mechanism of the gut nematode against the host immune response.
From: The Laboratory Mouse (Second Edition), 2012
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Mouse Models
Siân E. Piret, Rajesh V. Thakker, in Genetics of Bone Biology and Skeletal Disease, 2013
II Methods for Generating Mouse Models
Non-Targeted Strategies
Spontaneous mutations in mice may result in benign phenotypes such as variable coat colors, or in disorders that have similarities to diseases in humans, e.g. the hypophosphatamia (Hyp) mouse, which is representative of X-linked hypophosphatemia in humans.52 Such spontaneous mutations occur at very low frequencies, thus several techniques that increase the rate of mutation induction in the mouse genome by either non-targeted (random) or targeted strategies have been developed (see Tables 13.1 and 13.2). An early example of non-targeted mutagenesis is provided by irradiation, which generated the Gy mouse, a second model for X-linked hypophosphatemia.52 More recently, chemical mutagens have been used in large-scale mutagenesis programs. Successful agents include isopropyl methane sulfonate (iPMS) used to generate the Nuf mouse model with an activating calcium-sensing receptor (CaSR) mutation, and N-ethyl-N-nitrosourea (ENU) used to generate a mouse model for osteogenesis imperfecta with a collagen 1 alpha 1 (COL1A1) mutation. ENU, which is an alkylating agent that primarily introduces point mutations via transfer of the ENU alkyl group to the DNA base followed by mispairing and subsequent basepair substitution during the next round of DNA replication (Figure 13.1A), is the most potent mutagen in mice.14 Intraperitoneal injections of ENU to male mice generate approximately one mutation per 1–1.5 Mbp of sperm DNA,14 which allows the mutations to be inherited (Figure 13.1B). ENU mutagenesis programs utilize two complementary approaches, which are phenotype-driven and genotype-driven screens. In phenotype-driven screens, the offspring of mutagenized mice are assessed for phenotypic variances, using a panel of morphological, biochemical, or behavioral tests, in a “hypothesis-generating” strategy, which aims to elucidate new genes, pathways and mechanisms for a disease phenotype14 (Figure 13.1B). By establishing appropriate matings, phenotype-driven screens can be used to identify dominant or recessive phenotypes. Genotype-driven screens, in which mutations in a gene of interest are sought, are “hypothesis-driven” and are feasible by using available parallel archives of DNA and sperm samples from mutagenized male mice (Figure 13.1B). Archived DNA samples from the mutagenized male mice are used to search for mutations in the gene of interest, and once mutations are identified in the mouse DNA, then the corresponding sperm sample for the male mouse harboring the mutation is used to establish progeny carrying the mutation by in vitro fertilization.14 It is estimated that the probability of finding three or more mutant alleles in an archive of >5000 DNA samples is >90%.53 Thus, the gene-driven approach can be used to generate an “allelic series” of mutations within one gene, which may yield insights into genotype–phenotype correlations in the gene and disease of interest.54

ENU mutations most frequently result in missense mutations (>80%) that may generate hypo- and hypermorphs, although occasionally nonsense or frame-shift mutations (<10%) generating knockout models may be obtained.55 However, a more recent and reliable method for generating non-targeted knockout models on a large scale is by the use of insertional mutagenesis, utilizing gene-trap strategies.56,57 Gene-trap vectors usually consist of a reporter gene, either with or without a promoter, and a strong splice acceptor site, which causes any upstream exons to splice directly to the gene-trap15 (see Figure 13.1C). The vector is either electroporated or retrovirally infected into embryonic stem (ES) cells, after which it randomly inserts into the genome. Mutagenized ES cells are then re-introduced into developing blastocysts to generate chimeric mice, from which germline mutant mice can be bred (Figure 13.2). A recent refinement of the gene-trap strategy is targeted trapping, in which the vector also contains regions homologous to the targeted gene, thereby facilitating the deletion of a specific gene.16,56

Targeted Strategies
A specific loss of function (i.e. knockout) of a gene of interest in the germline can be generated to yield conventional targeted knockout models, as follows. A targeting construct is assembled, which contains two “arms” of sequence homologous to the gene of interest and that flank a positive selection cassette such as the E. coli neomycin phosphotransferase (NeoR) gene (Figure 13.3A). Integration of the NeoR gene (and therefore the targeting construct) into the ES cell genome allows these ES cells to survive normally toxic amounts of antibiotic treatment, thereby allowing selection of ES cells that have been successfully targeted by homologous recombination. Furthermore, replacement of an exon (or exons) by the NeoR cassette results in gene disruption, i.e. “knockout”17 (Figure 13.3A). To facilitate further the selection of ES cells that have undergone successful targeting by homologous recombination, a negative selection cassette, such as the Herpes simplex virus thymidine kinase (TK) gene, may also be used. The TK gene cassette is inserted at one end of the homologous region of the targeting construct, such that the TK cassette is lost if homologous recombination has occurred (Figure 13.3A), but retained if non-homologous recombination has occurred. In the presence of a thymidine analog in the growth medium, ES cells containing the TK cassette (i.e. following non-homologous recombination) will not undergo cell division, as the thymidine analog will undergo phosphorylation and will be incorporated into the DNA by the TK, and thereby disrupt cell division, hence selecting out these ES cells. In contrast, those ES cells that do not have the TK cassette (i.e. following homologous recombination) will not have disrupted cell division due to incorporation of the thymidine analog and, as a result, will proliferate.17 Correctly targeted ES cells are used to generate chimeric mice (see Figure 13.2), which are then bred with wild-type mice to yield mice with germline transmission of the disrupted allele, i.e. “knockout” mice, that have one copy of the disrupted allele in all of their cells. Cross-breeding of these heterozygous knockout mice can then yield homozygous knockout mice, which will have a disruption of both alleles of the gene in all of their cells. These “conventional” knockout models have proved to be very useful in studies of human diseases, although their use may be limited if the disruption of the gene in a critical organ results in early death, e.g. at any embryonic stage. To overcome such limitations, it may be useful to generate tissue-specific (i.e. conditional knockout) or time-specific (i.e. inducible knockout) models. This can be achieved by refining the gene-trap and “conventional” knockout strategies by the addition of either LoxP or flippase (FLP) recombinase target (FRT) sites in the targeting vector (Figure 13.3B). LoxP and FRT sites are short DNA sequences which are recognized and acted upon by the enzymes Cre (causes recombination) recombinase or FLP recombinase enzymes, respectively and, when inserted to flank the genomic region of interest, will result in either excision or inversion of the DNA flanked by the LoxP or FRT sequences, depending on whether the two sequences are in the same orientation (Figure 13.3B), or opposite orientations, respectively. Thus, insertion of the LoxP and FRT sequences allows several variations on the knockout mouse, including either tissue-specific (conditional) or time-specific (inducible) knockouts (see Table 13.2). Thus, if mice containing alleles in which the exon containing the start codon is flanked by LoxP sites (“floxed”) or FRT sites (“flirted”), are crossed with transgenic mice expressing Cre or FLP under the control of tissue-specific promoters (e.g. the PTH gene promoter for parathyroid-specific expression), the gene of interest can be knocked out in a specific tissue (Figure 13.3B). The inducible models utilize a fusion protein, such as a modified ligand-binding domain of the estrogen receptor fused to the Cre (CreER) or FLP gene which, on administration of an estrogen receptor antagonist (tamoxifen), translocates to the nucleus to excise the floxed allele(s), thereby allowing the gene to be permanently knocked out at the desired time, which may be either during embryonic or neonatal development, or in adult life.18 These conditional and inducible knockout mouse models have proved particularly useful to overcome embryonic or early postnatal lethality, for example in studies of Blomstrand’s chondrodysplasia due to PTHR1 loss of function (see Table 13.4), or to understand the role of a protein in one particular tissue.

Knockout mice have been very valuable for the study of physiological functions of proteins and the elucidation of disease mechanisms. However, knockout models are not always the most appropriate, particularly when the human disease being studied is not due to a loss of function or null allele for the gene. Indeed, the majority of human diseases are unlikely to be due to null alleles, but are instead associated with point mutations, which may result in a constitutively active protein, or a toxic gain of function, as illustrated by PTHR1 mutations in Jansen’s disease (see Table 13.4), or dominant negative effects. Thus, to generate appropriate murine models for these diseases, the specific mutation needs to be introduced into the mouse genome, and this may be achieved by targeted knock-in or transgenic approaches (see Tables 13.1 and 13.2). The generation of targeted knock-in models utilizes a similar approach to that described above for targeted knockout models, except that a targeting vector which carries the desired mutation must be specifically generated (see Figure 13.3C). In addition, the positive selection cassette is normally placed in an intron and floxed so that it can be excised and cause minimal effects on gene expression.19 The generation of transgenic models utilizes a targeting construct which usually contains the cDNA carrying the mutation, together with an appropriate promoter and poly(A) sequence, which is injected into the pronucleus of fertilizd mouse eggs.20,21 The transgene undergoes random insertion into the genome, and several copies are often inserted together, which therefore generates an overexpression model. As reviewed below, these different strategies for generating mouse models of human diseases have greatly facilitated studies of inherited bone and mineral disorders that have investigated mechanisms and treatments, which would not be easily feasible in patients.View chapterPurchase book
Mouse Models of The Nuclear Envelopathies and Related Diseases
Henning F. Horn, in Current Topics in Developmental Biology, 2014
9 Conclusions
Mouse models provide a valuable tool for studying human diseases. This has certainly been true for mouse models of LINC complex proteins and their associated diseases. The various Nesprin-1 mouse models have augmented our understanding of the underlying biology of muscular dystrophy, autosomal recessive arthrogryposis, and autosomal recessive cerebellar ataxia. The mouse models for the Nesprin-4-associated hearing loss were critical in elucidating the cell biology and provided key insights into this entirely novel class of human hearing loss. And mouse models of SUN1 and KASH5 have allowed us a greater appreciation for the importance of chromosomal movement in the development of gametes. Indeed, our mouse model-generated understanding of LINC complex functions may even prove to be predictive for human diseases. For example, a novel human disorder was recently described that has features of mandibular acral dysplasia but also includes deafness and male hypogonadism as prominent associated features (Shastry et al., 2010). Several candidate genes were examined, but no mutations were found to cause this genetic condition. However, given our knowledge of the roles of SUN1, and the phenotypes of the SUN1 mouse models (hearing loss and hypogonadism), it would be interesting to check the function of SUN1 in these patients.
While a number of mouse models now exist for LINC complex proteins, the field is still relatively young. Indeed, we are still discovering novel LINC complex functions and novel variants of LINC complexes. We therefore expect that future mouse models will continue to augment our understanding of the LINC complex in normal as well as pathophysiological roles.View chapterPurchase book
Alzheimer’s Disease: Transgenic Mouse Models
K.H. Ashe, in Encyclopedia of Neuroscience, 2009
Transgenic mouse models of Alzheimer’s disease (AD) have been created to study the structural and functional consequences of the accumulation of the amyloid-β and tau proteins in the brain. They have also been used to test experimental therapeutic interventions for AD. No transgenic mouse model perfectly represents all stages and facets of AD; transgenic mouse models cannot supplant the need for studying the disease in humans and human clinical trials. However, studies in transgenic mouse models allow researchers to understand aspects of the pathophysiology of AD and coordinate efforts to diagnose and treat the illness in humans.View chapterPurchase book
In Vitro and In Vivo Animal Models
Azka Khan, … Alvina Gul, in Omics Technologies and Bio-Engineering, 2018
18.2.13 Transgenic Mouse of PD
Mouse models have been a vital tool for research in neurodegenerative diseases. They have been proved as an effective model organism for PD. Both in vitro and in vivo mouse models have been extensively used. Many transgenic mouse models have been generated to study PD; α-synuclein protein has very important role in the pathology of this disease. KO mice and some transgenic mice with the ability to overexpress α-synuclein possess familial A53T or A30P mutations. α-Synuclein KO mice are viable and fertile, and they support a significant role of α-synuclein in regulation of dopaminergic neurotransmission, synaptic plasticity, and presynaptic vesicular release and recycling (Janus and Welzl, 2010).View chapterPurchase book
Biomarkers for Assessing Risk of Cancer
Xifeng Wu, Jian Gu, in The Molecular Basis of Cancer (Fourth Edition), 2015
Mouse Models for Cancer Susceptibility Study
Mouse models that cross tumor-resistant with tumor-susceptible strains have been instrumental in mapping several candidate cancer susceptibility loci and expression quantitative trait loci (eQTLs)125-131 before the wide application of GWAS in human cancers. Although hundreds of cancer susceptibility loci have been identified through GWAS, the majority of the heritable risk of cancer cannot be explained by the main effects of common alleles. Gene-gene and gene-environment interaction clearly play important roles in cancer development, which is challenging in human studies because of the heterogeneity of human cancers. Mouse models have a defined genetic background that does not possess the genetic heterogeneity characteristic of human cancers. Crossing genetically distinct mouse strains can allow the analysis of the combinatorial effects of host genetic background and somatic events at different stages of cancer development. A recent study applied a network analysis in a mouse model of skin cancer that produces both benign tumors and malignant carcinomas and identified a genetic architecture affecting inflammation and tumor susceptibility.132 Gene–environment interactions can also be investigated using mouse models to identify how genetic modifiers of tumor initiation interact with specific environmental effects identified through epidemiological studies. Mouse models will also be a major tool for mechanistic studies of cancer susceptibility loci.View chapterPurchase book
Molecular Basis of Lung Cancer
Mitsuo Sato, … John D. Minna, in The Molecular Basis of Cancer (Third Edition), 2008
New Transgenic Mouse Models of Lung Cancer
Mouse models that recapitulate the carcinogenic process of human lung cancer are powerful tools to improve our understanding of lung cancer pathogenesis, develop targeted therapeutics, and evaluate their in vivo efficacies. Several different types of transgenic mouse models for studying lung cancer have been developed with innovative strategies. Bitransgenic models using Cre/LoxP recombination or tetracycline-inducible gene expression system have enabled regulating the expression of a gene in mice in a timely and spatially controlled manner. Two groups engineered mouse strains harboring conditional mutant K-ras alleles that are expressed only after Cre/LoxP-mediated recombination occurs. Both groups showed that oncogenic K-ras activation induces lung adenocarcinoma, demonstrating the contributions of oncogenic K-ras to lung cancer pathogenesis (46). Moreover, Meuwissen et al. developed a mouse model of SCLC by inactivating both Rb and p53 using Cre/LoxP recombination system (46). Using a tetracycline-inducible gene expression system, mice harboring EGFR tyrosine kinase domain mutations were engineered. These mice developed adenocarcinomas very similar to human adenocarcinomas with EGFR mutations. Although there can be significant differences in lung tumor development between humans and mice, mouse models have a complete physiologic environment and allow analyzing host tumor interaction and angiogenesis, which cannot be studied in tissue culture. Finally, no mouse model of squamous cell carcinoma of the lung has been developed.View chapterPurchase book
Huntington Disease
Laura A. Wagner, … Blair R. Leavitt, in Animal and Translational Models for CNS Drug Discovery, 2008
Validity of Animal Models of HD
Mouse models of HD are important to the discovery and validation of drug targets for HD as well as central to proving drug efficacy preceding human therapeutic trials. The development and validation of an effective mouse model of disease is no trivial matter and requires extensive characterization and rigorous validation (see Table 6.2). The ideal mouse model for HD agrees in etiology, pathophysiology, symptomatology, and response to therapeutics when compared to the human condition. Originally, chemical models of HD were investigated based on their similar striatal neurodegenerative pattern as seen in human HD patients. These chemical models met the very basic symptomatology criterion alone. Since the discovery of the HD gene, however, more accurate gene models of HD have been developed as transgenic mice representing HD etiology, pathophysiology, and symptomatology. Although species differences complicate the exact phenotype comparisons that can be made, genetic HD mice overall recapitulate cognitive failure, motor dysfunction, and striatal neurodegeneration as seen in human HD patients.
Table 6.2. Validation of animal models of diseasea
Face validity- a superficial resemblance between the mouse model and human disease. A similarity seen in symptoms is a common justification in this case (e.g., chemical models of HD). |
Predictive validity- the ability of a model to predict the performance of the condition being modeled. One example is a model’s capacity to predict compound efficacy in therapeutic human trials. |
Construct validity- a theoretical clarification of what a model is supposed to represent. This validation accounts for the inherent difference that may occur in a process when looking across species. |
Etiological validity- in this case the model and the human condition must undergo identical etiologies. The simplest disease to model in this situation is that of a simple inheritance disease. |
aVan Dam and De Deyn. (2006). Drug discovery in dementia: The role of rodent models. Nat Rev: Drug Discov 5:956–970.
Three basic design strategies have been applied in developing HD gene mouse models giving rise to three broad model categories including: (i) fragment models containing N-terminal fragments of the human mutant Htt protein in addition to both alleles of murine Hdh, (ii) full-length models containing the full-length human HD gene with an expanded polyglutamine tract in addition to both alleles of murine Hdh, and (iii) knock-in models of HD with pathogenic CAG expansions in murine Hdh. Individually these gene models are believed to represent certain aspects of HD based on their design and phenotype. These characteristics help define the strength of the model and its subsequent use in the field of HD research. Together these different gene models provide confirmatory proof of the dysfunction and disease caused by a Htt CAG expansion in mice. As a result, HD gene mouse models provide a powerful analysis for target validation and drug discovery preceding clinical trials. To date, the fourth criterion of an ideal HD mouse model, its predictive power in identifying effective drugs for HD awaits verification by emerging and ongoing human clinical trials.View chapterPurchase book
Application of Mouse Genetics to Human Disease
Teresa M. Gunn, Brenda Canine, in Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015
Summary
Mouse models have led – and are certain to continue to lead – to significant breakthroughs in identifying genes, mechanisms, and pathways that underlie human neurologic diseases. Mice are also ideal for testing therapeutic approaches, something we are likely to see more of in the coming years. New methodologies have increased the speed and accuracy with which new mouse models can be generated, and technological advances have led to improved tools to analyze them. Models of multigenic disorders remain scarce. This is primarily because it is difficult to identify the variants that cause these traits, and most mouse models are presently generated using gene targeting, which requires the causative loci be known. Random mutagenesis and thorough phenotypic analysis (including behavioral studies) of existing mutants may reveal subtle and/or unexpected traits, and will complement other, ongoing projects aimed at discovering disease-associated variants in human populations. There is much excitement over the ability to reprogram fibroblasts or other patient-derived cells into induced pluripotent stem cells (iPSC), and the ability to differentiate those iPSC into neuronal stem cells allows for the analysis of those cells in culture. Injecting these cells into the mouse brain will create a new class of mouse models that will provide insight into the in vivo behavior of patient-derived cells in the mammalian nervous system. Combining these models with existing genetic models and reporter mice will create a powerful system for analyzing the pathogenesis of neurological disorders.View chapterPurchase book
Gsα, Pseudohypoparathyroidism, Fibrous Dysplasia, and McCune–Albright Syndrome
Lee S. Weinstein, Michael T. Collins, in Genetics of Bone Biology and Skeletal Disease (Second Edition), 2018
3.4 Animal Models
Mouse models leading to constitutively activation of cAMP formation have been created by transgenic overexpression of Gsα, by expression of R201H or Q227L mutant forms of Gsα, or by expression of the cholera toxin A1 subunit, which covalently modifies R201 (Fig. 35.1). Transgenic expression of the cholera toxin A1 subunit in somatotrophs leads to pituitary hyperplasia and gigantism, whereas expression in thyroid cells leads to thyroid hyperplasia and hyperthyroidism.109 Gsα overexpression in the heart leads to cardiomyopathy,110 and expression of constitutively-activated forms of Gsα in the forebrain disrupts associative and spatial learning.111 A model of FD was created by transplanting Gsα-mutated skeletal progenitor cells into immunocompromised mice.112 A mouse model with germline expression of the R201C mutation survived, and with aging developed a skeletal dysplasia radiographically and histologically similar to FD.113View chapterPurchase book
Gsα, Pseudohypoparathyroidism, Fibrous Dysplasia, and McCune–Albright Syndrome
Lee S. Weinstein, … Allen M. Spiegel, in Genetics of Bone Biology and Skeletal Disease, 2013
Animal Models
Mouse models leading to constitutively activation of cAMP formation have been created by transgenic overexpression of Gsα, by expression of R201H or Q227L mutant forms of Gsα, or by expression of the cholera toxin A1 subunit which covalently modifies R201 (see Figure 27.1). Transgenic expression of the cholera toxin A1 subunit in somatotrophs leads to pituitary hyperplasia and gigantism, whereas expression in thyroid cells leads to thyroid hyperplasia and hyperthyroidism.73 Gsα overexpression in the heart leads to cardiomyopathy,74 and expression of constitutively-activated forms of Gsα in the forebrain disrupts associative and spatial learning.75 A model of FD was created by transplanting Gsα-mutated skeletal progenitor cells into immunocompromised mice.76 A mouse model replicating the full MAS phenotype has not been reported, perhaps because of the adverse effects of more generalized cAMP activation on normal development.View chapterPurchase book
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