Genetics of Diabetes in the Amish

描述(由申请人提供)：这是针对美国国立卫生研究院NOT-OD-09-058通知的竞争修订申请。父母赠款的标题是“阿米什人糖尿病的遗传学”(R01 DK04261；舒尔迪纳，PI)。拟议的研究建立在父母拨款的基础上，并扩大了其具体目标、研究设计和方法的范围。具体地说，父母赠款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上的基因(S)，该基因与阿米什人和其他几个群体中的2型糖尿病(T2D)有关。这项工作确定一氧化氮合酶相关蛋白1(NOS1AP)是一个可能与人类2型糖尿病和肥胖症有关的基因。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缺陷对肥胖和新陈代谢的功能后果。我们假设NOS1AP基因敲除(KO)小鼠与其野生型小鼠相比，体重增加、胰岛素分泌改变、葡萄糖不耐受/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(德克萨斯州A&M基因组医学研究所)中培育出纯合子NOS1AP KO小鼠。这些小鼠和它们的野生型后代将接受正常饮食和高脂肪饮食。代谢表型，其中一些将在NIDDK资助的耶鲁大学小鼠代谢表型中心进行，将包括身体成分、食物摄入量、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，这将首次暗示NOS1AP是糖脂代谢和能量平衡的重要调节因素，这可能对设计新的T2D和相关代谢并发症的预防和治疗措施具有重要意义。根据2009年《美国复苏和再投资法案》的授权，这一竞争性修订的资金将通过为专业和技术人员提供就业机会和保障，通过在马里兰大学购买用品、试剂和服务，以及通过服务安排费用(也是在耶鲁大学医学院和德克萨斯农工大学)来刺激经济。此外，它将加快糖尿病研究的步伐，这可能导致与改善治疗和预防T2D相关的长期成本节约。 与公共健康相关：2型糖尿病和肥胖症是美国的主要公共健康问题，造成巨大的发病率、死亡率和医疗费用。这项工作可能提供新的机制洞察，导致新的和更有效的治疗和预防策略。此外，作为美国复苏和再投资法案的一部分，这一竞争性修订将提供就业机会和保障，并刺激经济。

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.