The Collaborative Cross Project of Diabetes

描述(由申请人提供)： 项目摘要/摘要我们正处于一场史无前例的2型糖尿病(T2 DM)流行之中。仅在一代人的时间里，患有T2 DM的人口比例就翻了一番。虽然这一流行病主要是由肥胖引起的，但只有约20%的肥胖者会患上T2 DM。遗传因素在决定肥胖者中谁会发展成T2 DM方面起着主要作用。T2 DM的遗传度估计约为0.5。人类的遗传学研究已经确定了许多与糖尿病易感性有关的基因座。几乎所有这些基因座都与细胞生物学有关。然而，这些基因座只占T2 DM高遗传度的一小部分。这项拨款提案的一个指导前提 人类糖尿病遗传学“缺失遗传性”的一个重要来源是无法对β细胞功能进行深入的机械性表型分析。在这里，我们建议对胰岛进行深入的表型分析，以确定与T2 DM易感性相关的基因和途径。该项目涉及一种杂交策略，使用两个互补的小鼠遗传队列：1)远交小鼠群体和2)重组近交系(RI)品系，两者都来自相同的创始人群体。这个群体，合作十字，是由8个方正品系衍生而来，这些品系共同捕捉了近亲交配小鼠品系中可用遗传变异的主要部分。我们对创始菌株的初步研究显示，与糖尿病易感性相关的性状具有高度的表型多样性。这些结果预测，我们建议研究的性状将具有很强的遗传力。我们的团队由一个在胰岛生物学和糖尿病遗传学方面拥有丰富经验的实验室和四名统计遗传学家组成，他们开发了许多广泛使用的QTL定位和因果网络构建方法。我们将开展胰岛素分泌、β细胞增殖和氧化代谢的研究。此外，我们还将对分离的胰岛进行转录组、蛋白质组和磷蛋白质组学研究。除了经典的关联作图，我们还将使用遗传关联数据来构建将基因座位与中间性状和疾病表型联系起来的因果网络。根据我们之前成功的位置克隆项目的经验，我们预测我们识别的基因座将与人类对糖尿病的易感性高度相关。

DESCRIPTION (provided by applicant): Project Summary/Abstract We are in the midst of an unprecedented epidemic of type 2 diabetes (T2DM). The proportion of the population with T2DM has doubled in just one generation. Although the epidemic is primarily driven by obesity, only ~20% of obese individuals develop T2DM. Genetic factors play a major role in determining who among obese individuals will progress to develop T2DM. The heritability of T2DM has been estimated to be approximately 0.5. Genetic studies in humans have identified many loci that contribute to diabetes susceptibility. Nearly all of these loci are involved in ¿-cell biology. However, these loci only account for a small part of the high heritability of T2DM. A guiding premise of this grant proposal is that an important source of the "missing heritability" of human diabetes genetics is the inabiliy to carry out in-depth mechanistic phenotyping of beta-cell function. Here, we propose to carry out deep phenotyping of pancreatic islets to identify genes and pathways that confer susceptibility to T2DM. The project involves a hybrid strategy, employing two complementary mouse genetic cohorts: 1) a population of outbred mice and 2) a panel of recombinant inbred (RI) strains, both derived from the same founder population. This population, The Collaborative Cross, was derived from eight founder strains that together capture a major part of the genetic variability available in inbred mouse strains. Our preliminary studies of the founder strains revealed a high degree of phenotypic diversity in traits related to diabetes susceptibility. These results predict that the traits we propose to study will have strong heritability. Our team consist of a laboratory with extensive experience in islet biology and diabetes genetics together with four statistical geneticists who have developed many of the widely used methods for QTL mapping and causal network construction. We will carry out studies of insulin secretion, beta-cell proliferation and oxidative metabolism. In addition, we will conduct transcriptomic, proteomic, and phosphoproteomic studies on isolated pancreatic islets. In addition to classical association mapping, we will use genetic association data to construct causal networks linking gene loci with intermediate traits and disease phenotypes. Based on our prior experience with successful positional cloning projects, we predict that the loci we identify will be highly relevan to diabetes susceptibility in humans.