Molecular Genetics of Mouse Models for Type II Diabetes

描述（由申请人提供）：超重和肥胖的患病率在工业化国家达到约30%，并且肥胖连同相关的代谢紊乱、胰岛素抵抗和II型糖尿病（T2 D）是不断增长的主要健康问题。像肥胖一样，T2 D具有很强的遗传成分，被认为是多基因与环境相互作用的结果。因此，在人类中具有主要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，并且在识别肥胖小鼠模型中突变的基因方面取得了显着进展。小鼠突变的真实的价值在于它们提供了进入新的代谢和调节途径的途径，这些途径涉及人类糖尿病和相关疾病的病因学。需要定义或识别新型T2 D通路的新模型，以进一步了解这种慢性且通常危及生命的疾病。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，并有公认的专业知识，以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II型糖尿病新小鼠模型TallyHo（TH）株，并对其进行了生物化学和遗传学表征。TH菌株的特征在于葡萄糖耐受不良、高胰岛素血症、慢性高血糖症、体重增加和活动水平降低。TH是目前唯一一种自发性单基因突变tanidd 1触发T2 D的模型。此外，让人联想到人类的情况，主要基因座与额外的背景肥胖和糖尿病易感基因相互作用，产生明显的糖尿病。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背景下以同源菌株的形式产生了资源。我们还确定了一个强大的tanidd 1的分子亚表型，使其鉴定的位置克隆可行。为了获得对T2 D途径的新见解，我们建议：a）定位克隆TH中存在的糖尿病易感基因tanidd 1; B）以衍生自TH的同类菌株的形式产生T2 D亚表型的新模型并对其进行生理学表征; c）确定这些基因之间的相互作用具有什么样的表型后果。在这项工作的成功结束时，我们将确定一种新的糖尿病易感基因，并提供新的，充分表征的T2 D亚表型模型，这将导致对T2 D病因的新见解。

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.