Molecular Genetics of Mouse Models for Type II Diabetes

描述(申请人提供)：在工业化国家，超重和肥胖的流行率约为30%，肥胖及其相关的代谢紊乱、胰岛素抵抗和II型糖尿病(T2D)日益增长，是主要的健康问题。像肥胖一样，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，在识别肥胖小鼠模型中突变的基因方面也取得了显著进展。小鼠突变的真正价值在于它们提供了进入新的代谢和调节途径的途径，这些途径涉及人类肥胖和相关疾病的病因学。需要新的模型来定义或识别新的T2D通路，以加深我们对这种慢性且通常威胁生命的疾病的理解。我们在杰克逊实验室处于独特的地位，可以发现和开发新的肥胖症/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II型糖尿病小鼠模型，并在生化和遗传学方面进行了表征，Tallyho(Th)品系。TH菌株的特征是葡萄糖耐受、高胰岛素血症、慢性高血糖、体重增加和活动水平降低。这是目前唯一一个自发的单基因突变tanidd1触发T2D的模型。此外，与人类的情况类似，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。为了促进位置克隆和评估相互作用的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型，使得通过定位克隆来鉴定它是可行的。为了获得对T2D途径的新认识，我们建议：a)定位克隆存在于TH中的糖尿病易感基因tanidd1；b)以TH衍生的同源菌株的形式建立T2D亚型的新模型，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表型后果。在这项工作的成功结束时，我们将发现一个新的糖尿病易感基因，并提供新的、具有良好特征的T2D亚型模型，这将导致对T2D病因学的新见解。

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.