Characterizing and Cloning Obesity and Diabetes Genes

简介（由申请人提供）：在工业化国家，超重和肥胖的患病率达到30%左右，肥胖及其相关的代谢紊乱、胰岛素抵抗和非胰岛素依赖型糖尿病是日益严重的健康问题。肥胖有很强的遗传成分，被认为是多基因与环境相互作用的结果。因此，人们花了很多精力试图找出导致人类常见肥胖形式的基因，然而，还没有发现有主要影响的基因。相比之下，在识别引起肥胖的单基因突变方面取得了显著进展。尤其是小鼠肥胖模型中基因突变的特征极大地促进了我们对这种疾病的理解。小鼠突变的价值在于它们提供了涉及人类肥胖和相关疾病病因学的新代谢和调节途径。需要新的模型来进一步定义或识别新的肥胖途径，以扩大我们对这种慢性疾病及其有时危及生命的相关并发症的理解。在杰克逊实验室，我们处于一个独特的位置，可以发现这种新的肥胖/ 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。我们的机构偏差搜索计划和两个NIH资助的突变中心是新突变的丰富资源。辅助生殖技术的引入使我们能够快速有效地生产实验动物，用于表型表征和基因杂交，以绘制和克隆突变。小鼠基因组的完成大大加快了突变检测。我们现在可以利用这些技术进步，为研究界带来新的、具有良好特征的小鼠肥胖模型。我们初步选择了5个新的小鼠肥胖突变进行定位克隆。这些新的突变涵盖了从早发到晚发、中度或病态、伴有或不伴有II型糖尿病的一系列肥胖表型。在这项工作的成功结束后，我们将确定至少五个新的肥胖和糖尿病基因，提供足够的表型信息，使这些模型对肥胖/糖尿病研究界有用，并形成和测试关于它们功能的假设。

DESCRIPTION (provided by applicant): The prevalence of overweight and obesity reaches ~30% in industrialized countries, and obesity together with the related metabolic disorders, insulin resistance and non insulin dependent diabetes mellitus are ever growing and major health problems. Obesity has a strong genetic component and is thought to be the result of the interaction of polygenes with the environment. Consequently, much effort has gone into trying to identify genes responsible for the common forms of human obesity, however, no gene with a major effect has been identified. In contrast, remarkable progress has been made in the identification of single gene mutations causing obesity. Particularly the characterization of the genes mutated in mouse models of obesity has greatly contributed to our understanding of the disease. The value of the mouse mutations lies in the access they provide to novel metabolic and regulatory pathways involved in the etiology of obesity and related disorders in humans. New models that will further define or identify novel obesity pathways are needed to expand our understanding of this chronic disease and its sometimes life threatening associated complications. We are in a unique position at The Jackson Laboratory to discover such new obesity/type 2 diabetes models and have the proven expertise to identify their underlying molecular bases. Our institutional Deviant Search program and two NIH funded mutagenesis centers are a rich resource for new mutations. The introduction of assisted reproductive technologies allows us to quickly and efficiently produce experimental animals for phenotypic characterization and for genetic crosses to map and clone the mutations. The completion of the mouse genome greatly accelerates mutation detection. We can now capitalize on these technical advances to bring new, well-characterized mouse obesity models to the research community. We have initially selected five new mouse obesity mutations for positional cloning. These new mutations cover a spectrum of obesity phenotypes from early to late onset, moderate or morbid, and with or without accompanying type II diabetes. At the successful conclusion of this work, we will have identified at least five new obesity and diabetes genes, provided sufficient phenotypic information to make these models useful to the obesity/diabetes research community, and formed and tested hypotheses regarding their function.