Genetics of Diabetes in the Amish

阿米什人的糖尿病遗传学

• 批准号: 7844255
• 负责人: ALAN R. SHULDINER
• 金额: $ 11.54万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844255
• 关键词: 1q21; Adaptor Signaling Protein; Adipose tissue; American; Amish; Blood Glucose; Body Composition; Body mass index; Brain; Breeding; Candidate Disease Gene; Chromosomes; Classification; Cost Savings; Data; Diabetes Mellitus; Diet; ES Cell Line; Eating; Electrocardiogram; Energy Metabolism; Fasting; Fatty acid glycerol esters; Fee-for-Service Plans; Funding; Future; Genes; Genetic Polymorphism; Genomics; Genotype; Glucose; Glucose Intolerance; Glucose tolerance test; Health Care Costs; Heart; Hepatocyte; Homeostasis; Human; Human Genetics; Hyperlipidemia; Injection of therapeutic agent; Institutes; Insulin; International; Intervention; Islets of Langerhans; Knock-out; Knockout Mice; Lead; Letters; Linkage Disequilibrium Mapping; Lipids; Lipoproteins; Liver; Maryland; Medicine; Metabolic; Metabolism; Methods; Molecular; Morbidity - disease rate; Mus; Muscle; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Occupations; Pathogenesis; Phenotype; Play; Population; Prevention; Prevention strategy; Proteins; Public Health; Reagent; Recovery; Reporting; Research; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Schizophrenia; Security; Services; Signal Transduction; Small Interfering RNA; Texas; Time; Tissues; Triglycerides; United States National Institutes of Health; Universities; Variant; Weight Gain; Western Blotting; Work; base; design; diabetes mellitus genetics; disease phenotype; embryonic stem cell; genetic association; genome wide association study; glucose tolerance; improved; in vivo; insight; insulin secretion; insulin sensitivity; intraperitoneal; lipid biosynthesis; lipid metabolism; medical schools; mortality; mouse model; novel; parent grant; public health relevance; response; sudden cardiac death; treatment strategy

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.

描述（由申请人提供）：这是响应 NIH 通知 NOT-OD-09-058 的竞争性修订请求。家长资助的标题是“阿米什人糖尿病的遗传学”（R01 DK04261；Shuldiner，PI）。拟议的研究以家长资助的发现为基础，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，定位染色体 1q21-q24 上与阿米什人和其他几个人群中的 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。此次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 缺陷对肥胖和代谢的功能影响。我们假设，与野生型同窝小鼠相比，Nos1ap 敲除 (KO) 小鼠体重增加、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（德克萨斯 A&M 基因组医学研究所）产生纯合 Nos1ap KO 小鼠。这些小鼠及其野生型同窝小鼠将接受正常饮食和高脂肪饮食。代谢表型分析（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、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。如果我们的假设正确，这将首次表明 NOS1AP 作为糖脂代谢和能量稳态的重要调节因子，这可能对 T2D 和相关代谢并发症的新预防和治疗干预措施的设计具有重要意义。 根据 2009 年《美国复苏和再投资法案》的规定，此次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，以及在马里兰大学购买用品、试剂和服务，以及在耶鲁大学医学院和德克萨斯农工大学收取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，从而可以节省与改善 T2D 治疗和预防相关的长期成本。 公共卫生相关性：2 型糖尿病和肥胖是美国主要的公共卫生问题，造成巨大的发病率、死亡率和医疗保健费用。这项工作可能提供新颖的机制见解，从而产生新的、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。

项目成果

Analysis of the bereavement effect after the death of a spouse in the Amish: a population-based retrospective cohort study.

阿米什人配偶去世后的丧亲效应分析：一项基于人群的回顾性队列研究。

• DOI: 10.1136/bmjopen-2013-003670
• 发表时间: 2014
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Seifter,Ari;Singh,Sarabdeep;McArdle,PatrickF;Ryan,KathleenA;Shuldiner,AlanR;Mitchell,BraxtonD;Schäffer,AlejandroA
• 通讯作者: Schäffer,AlejandroA

Genome-wide scan of obesity in the Old Order Amish.

对旧秩序阿米什人的肥胖进行全基因组扫描。

• DOI: 10.1210/jcem.86.3.7358
• 发表时间: 2001
• 期刊: The Journal of clinical endocrinology and metabolism.
• 作者: Hsueh,WC;Mitchell,BD;Schneider,JL;StJean,PL;Pollin,TI;Ehm,MG;Wagner,MJ;Burns,DK;Sakul,H;Bell,CJ;Shuldiner,AR
• 通讯作者: Shuldiner,AR

Evaluation of A2BP1 as an obesity gene.

• DOI: 10.2337/db09-1604
• 发表时间: 2010-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Ma L;Hanson RL;Traurig MT;Muller YL;Kaur BP;Perez JM;Meyre D;Fu M;Körner A;Franks PW;Kiess W;Kobes S;Knowler WC;Kovacs P;Froguel P;Shuldiner AR;Bogardus C;Baier LJ
• 通讯作者: Baier LJ

Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.

• DOI: 10.2337/db09-1593
• 发表时间: 2010-08
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Muller YL;Hanson RL;Bian L;Mack J;Shi X;Pakyz R;Shuldiner AR;Knowler WC;Bogardus C;Baier LJ
• 通讯作者: Baier LJ

Epigenetic Signature of Impaired Fasting Glucose in the Old Order Amish.

旧秩序阿米什人空腹血糖受损的表观遗传特征。

• DOI: 10.21767/2472-1158.100052
• 发表时间: 2017
• 期刊: Journal of clinical epigenetics
• 作者: Montasser,MayE;Cheng,Yu-Ching;Tanner,Keith;Shuldiner,AlanR;O'Connell,JeffreyR
• 通讯作者: O'Connell,JeffreyR