Molecular Genetics of Mouse Models for Type II Diabetes

II 型糖尿病小鼠模型的分子遗传学

• 批准号: 7251471
• 负责人: JUERGEN K. NAGGERT
• 金额: $ 31.54万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251471
• 关键词: Affect; Age; Alleles; Animal Model; Area; Biochemical; Candidate Disease Gene; Cell surface; Chromosome Mapping; Chronic; Cloning; Congenic Mice; Congenic Strain; Defect; Developed Countries; Diabetes Mellitus; Disease; Environment; Etiology; Exocrine pancreatic insufficiency; Functional disorder; GLUT4 gene; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Crosses; Glucose Intolerance; Glucose Transporter; Health; Homeostasis; Human; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Laboratories; Lead; Leptin; Life; Localized; Maps; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Genetics; Mus; Mutate; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overweight; Pathway interactions; Phenotype; Population; Positioning Attribute; Predisposition; Prevalence; Quantitative Trait Loci; Regulatory Pathway; Resolution; Resources; Signal Pathway; Susceptibility Gene; Testing; Thinking; Transgenic Organisms; Week; Weight Gain; Work; base; congenic; genetic analysis; genome sequencing; insight; insulin signaling; male; mouse model; mutant; novel; positional cloning; research study; trait

DESCRIPTION (provided by applicant): The prevalence of overweight and obesity reaches approximately 30% in industrialized countries, and obesity together with the related metabolic disorders, insulin resistance and type II diabetes mellitus (T2D) are ever growing and major health problems. Like obesity, T2D has a strong genetic component and is thought to be the result of the interaction of polygenes with the environment. Consequently, genes with a major effect have yet to be identified in humans. In contrast, cloning of obesity and diabetes genes in the mouse is much easier and remarkable progress has been made in the identification of the genes mutated in mouse models of obesity. The real value of the mouse mutations lies in the access they provide to novel metabolic and regulatory pathways involved in the etiology of diabesity and related disorders in humans. New models that will define or identify novel T2D pathways are needed to further our understanding of this chronic and often life threatening disease. We are in a unique position at The Jackson Laboratory to discover and develop new obesity/type 2 diabetes models and have the proven expertise to identify their underlying molecular bases. In the past we have established, and biochemically and genetically characterized, a unique new mouse model for type II diabetes, the TallyHo (TH) strain. The TH strain is characterized by glucose intolerance, hyperinsulinemia, chronic hyperglycemia, increased body weight and reduced activity levels. TH is currently the only model in which a spontaneous single gene mutation, tanidd1, triggers T2D. In addition, reminiscent of the situation in humans, the major locus interacts with additional background obesity and diabetes susceptibility genes to produce overt diabetes. To facilitate positional cloning and to evaluate the contribution of the interacting genes to the overall phenotype, we have generated resources in the form of congenic strains on the common B6 background. We have also identified a robust molecular subphenotype for tanidd1, making its identification by positional cloning feasible. In order to gain new insights into T2D pathways we propose to: a) positionally clone the diabetes susceptibility gene tanidd1 present in TH; b) generate new models for subphenotypes of T2D in the form of congenic strains derived from TH and characterize them physiologically; c) determine what phenotypic consequences the interactions between these genes have. At the successful conclusion of this work, we will have identified a novel diabetes susceptibility gene and provided new, well characterized models of T2D subphenotypes that will lead to new insights into the etiology of T2D.

描述（由申请人提供）：在工业化国家，超重和肥胖的患病率约为30%，肥胖连同相关的代谢紊乱、胰岛素抵抗和II型糖尿病（T2D）日益增长，是主要的健康问题。与肥胖一样，T2D也有很强的遗传成分，被认为是多基因与环境相互作用的结果。因此，对人类有重大影响的基因尚未被确定。相比之下，在小鼠中克隆肥胖和糖尿病基因要容易得多，而且在小鼠肥胖模型中突变基因的鉴定方面取得了显著进展。小鼠突变的真正价值在于它们提供了与人类糖尿病和相关疾病的病因有关的新的代谢和调节途径。需要新的模型来定义或识别新的T2D通路，以进一步了解这种慢性且经常危及生命的疾病。我们在杰克逊实验室处于一个独特的位置，发现和开发新的肥胖/ 2型糖尿病模型，并拥有成熟的专业知识来确定其潜在的分子基础。在过去，我们已经建立了一种独特的2型糖尿病小鼠模型，TallyHo （TH）菌株，并对其进行了生化和遗传表征。TH菌株的特点是葡萄糖耐受不良、高胰岛素血症、慢性高血糖、体重增加和活动水平降低。TH是目前唯一由自发性单基因突变tanidd1引发T2D的模型。此外，与人类的情况类似，主要基因座与其他背景肥胖和糖尿病易感基因相互作用，产生显性糖尿病。为了便于定位克隆和评估相互作用基因对整体表型的贡献，我们在共同的B6背景上以同源菌株的形式产生了资源。我们还鉴定了tanidd1的一个强大的分子亚表型，使其通过定位克隆鉴定成为可能。为了获得关于T2D通路的新见解，我们建议：a)定位克隆TH中存在的糖尿病易感基因tanidd1；b)以TH同源菌株的形式建立新的T2D亚表型模型，并对其进行生理表征；C)确定这些基因之间的相互作用会产生什么样的表型结果。在这项工作的成功结论中，我们将确定一种新的糖尿病易感基因，并提供新的，表征良好的T2D亚表型模型，这将导致对T2D病因学的新见解。