The Collaborative Cross Project of Diabetes

糖尿病协作交叉项目

• 批准号: 8823773
• 负责人: Alan D Attie
• 金额: $ 42.04万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823773
• 关键词: Accounting; Affect; Animal Model; Applications Grants; Architecture; Beta Cell; Biology; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Cellular biology; Data; Diabetes Mellitus; Disease; Epidemic; Exocytosis; Founder Generation; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Glucose; Glucose Intolerance; Health; Heritability; Human; Human Genetics; Hybrids; Inbred Strains Mice; Inbreeding; Individual; Insulin; Insulin Resistance; Intervention; Investigation; Islets of Langerhans; Laboratories; Link; Maps; Measurement; Measures; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Phenotype; Physiological; Play; Population; Predisposition; Proteome; Proteomics; Quantitative Trait Loci; RNA Sequences; Recombinant Inbred Strain; Recombinants; Regulator Genes; Resolution; Resources; Respiration; Role; Source; Statistical Methods; Susceptibility Gene; System; Techniques; Testing; Therapeutic; Work; abstracting; base; causal model; cohort; design; detection of nutrient; diabetes mellitus genetics; disease phenotype; environmental stressor; experience; falls; gene discovery; genetic association; genome-wide; genome-wide analysis; in vivo; insulin secretion; islet; mouse model; network models; novel; positional cloning; protein transport; response; trait; transcriptome sequencing; transcriptomics

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.

描述（由申请人提供）： 项目摘要/摘要 我们正处于 2 型糖尿病 (T2DM) 史无前例的流行之中，尽管这种流行病主要是由肥胖引起的，但仅约 20% 的人患有 T2DM。遗传因素在决定肥胖个体中哪些人会发展为 T2DM 方面发挥着重要作用。人类遗传研究估计 T2DM 的遗传率约为 0.5。几乎所有这些基因座都参与糖尿病易感性。然而，这些基因座仅占 T2DM 高遗传力的一小部分。这是本拨款提案的指导前提。 人类糖尿病遗传学“遗传性缺失”的一个重要根源是无法对β细胞功能进行深入的机制表型分析。在这里，我们建议对胰岛进行深度表型分析，以识别影响胰岛功能的基因和通路。该项目涉及一种混合策略，采用两个互补的小鼠遗传群体：1) 一群远交小鼠和 2) 一组重组小鼠。近交 (RI) 品系，均源自相同的创始群体。这个群体（协作杂交）源自八个创始品系，它们共同捕获了近交系小鼠品系中可用的遗传变异的主要部分。揭示了与糖尿病易感性相关的性状的高度表型多样性，这些结果预测我们打算研究的性状将具有很强的遗传性。我们的团队由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以及四位统计遗传学家组成。有开发了许多广泛使用的 QTL 作图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学、蛋白质组学和磷酸化蛋白质组学研究。除了经典的关联作图之外，我们还将使用遗传关联数据构建将基因位点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定位克隆项目的经验，我们预测我们将识别的位点。与人类糖尿病易感性高度相关。