Genetics of Diabetes in the Amish

描述（由申请人提供）：这是对NIH通知no - od -09-058的竞争性修订请求。父母补助金的标题是“阿米什人的糖尿病遗传学”（R01 DK04261; Shuldiner， PI）。拟议的研究建立在父母资助的发现基础上，并扩大了其具体目标、研究设计和方法的范围。具体来说，父母资助的重点是在人类样本中应用高通量基因组方法来定位染色体1q21-q24上与阿米什人和其他人群中2型糖尿病（T2D）相关的基因。这项工作确定了一氧化氮合酶相关蛋白1 （NOS1AP）是一个可能与人类2型糖尿病和肥胖有关的基因。这项竞争性修订的目的是将这些发现扩展到小鼠模型中，以探索Nos1ap缺乏对肥胖和代谢的功能影响。我们假设Nos1ap基因敲除（KO）小鼠与野生型小鼠相比，体重增加、胰岛素分泌改变、葡萄糖耐受不良/糖尿病和高脂血症的倾向增加。我们将从先前建立的Nos1ap KO胚胎干细胞系（Texas A&M Institute of Genomic Medicine）中产生纯合子Nos1ap KO小鼠。这些小鼠和它们的野生型幼崽将接受正常的食物和高脂肪的饮食。代谢表型，其中一些将在niddk资助的耶鲁小鼠代谢表型中心进行，将包括身体组成，食物摄入，能量消耗，葡萄糖耐量，胰岛素分泌，胰岛素敏感性和脂质稳态。如果我们的假设是正确的，这将首次表明NOS1AP是糖脂代谢和能量稳态的重要调节因子，这可能对设计新的预防和治疗T2D及相关代谢并发症的干预措施具有重要意义。根据2009年《美国复苏与再投资法案》的规定，这项竞争性修订的资金将通过为专业技术人员提供就业机会和安全保障，以及通过在马里兰大学购买用品、试剂和服务，以及通过在耶鲁大学医学院和德克萨斯农工大学支付服务安排费用，来刺激经济。此外，它将加快糖尿病研究的步伐，这可能导致与改善t22d治疗和预防相关的长期成本节约。

DESCRIPTION (provided by applicant): This is a request for a Competitive Revision in response to NIH Notice NOT-OD-09-058. The parent grant is entitled "Genetics of Diabetes in the Amish" (R01 DK04261; Shuldiner, PI). The proposed study builds upon findings from the parent grant and expands the scope of its specific aims, research design, and methods. Specifically, the focus of the parent grant is to apply high throughput genomic approaches in human samples to localize the gene(s) on chromosome 1q21-q24 responsible for linkage to type 2 diabetes (T2D) in the Amish and several other populations. This work identified nitric oxide synthase associated protein 1 (NOS1AP) as a gene likely to be involved in human type 2 diabetes and obesity. The objective of this competitive revision is to extend these findings into a mouse model to explore the functional consequences of Nos1ap deficiency on obesity and metabolism. We hypothesize that Nos1ap knockout (KO) mice will have increased propensity for weight gain, altered insulin secretion, glucose intolerance/diabetes, and hyperlipidemia compared to its wild type littermates. We will generate homozygous Nos1ap KO mice from a previously established Nos1ap KO embryonic stem cell line (Texas A&M Institute of Genomic Medicine). These mice and their wild type littermates will be subjected to normal chow and high fat diets. Metabolic phenotyping, some of which will be performed at the NIDDK-funded Yale Mouse Metabolic Phenotyping Center, will include body composition, food intake, energy expenditure, glucose tolerance, insulin secretion, insulin sensitivity, and lipid homeostasis. If our hypothesis is correct, it would implicate for the first time NOS1AP as an important regulator of glucose and lipid metabolism and energy homeostasis, which may have important implications for the design of new prevention and treatment interventions for T2D and related metabolic complications. As mandated by the American Recovery and Reinvestment Act of 2009, funding of this competitive revision will stimulate the economy by providing job opportunities and security for professional and technical staff and through purchase of supplies, reagents and services at the University of Maryland, and through fee for service arrangements, also at Yale University School of Medicine and Texas A & M University. Furthermore, it will accelerate the pace of diabetes research, which could lead to long-term costs savings associated with improved treatment and prevention of T2D. PUBLIC HEALTH RELEVANCE: Type 2 diabetes and obesity are major U.S. public health problems that inflict enormous morbidity, mortality and health care costs. This work may provide novel mechanistic insights leading to new and more effective strategies for treatment and prevention. In addition, as part of the American Recovery and Reinvestment Act, this Competitive Revision will provide job opportunities and security and stimulate the economy.