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）：这是对NIH通知NOT-OD-09-058的竞争性修订请求。父母补助金的标题是“阿米什人糖尿病的遗传学”（R 01 DK 04261; Shuldiner，PI）。拟议中的研究建立在从父母补助金的调查结果，并扩大其具体目标，研究设计和方法的范围。具体而言，父母资助的重点是在人类样本中应用高通量基因组方法，以定位染色体1 q21-q24上负责与Amish和其他几个人群中的2型糖尿病（T2 D）联系的基因。这项工作确定了一氧化氮合酶相关蛋白1（NOS 1AP）作为可能参与人类2型糖尿病和肥胖的基因。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Nos 1ap缺乏对肥胖和代谢的功能后果。我们假设，Nos 1ap基因敲除（KO）小鼠将有增加的倾向，体重增加，改变胰岛素分泌，葡萄糖耐受不良/糖尿病，和高脂血症相比，其野生型同窝仔。我们将从先前建立的Nos 1ap KO胚胎干细胞系（Texas A&M Institute of Genomic Medicine）中产生纯合子Nos 1ap KO小鼠。这些小鼠及其野生型同窝小鼠将接受正常饲料和高脂肪饮食。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，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，这将首次涉及NOS 1AP作为葡萄糖和脂质代谢和能量稳态的重要调节剂，这可能对T2 D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》的规定，为这一竞争性修订提供资金将通过为专业和技术人员提供就业机会和保障，通过在马里兰州大学购买用品、试剂和服务，以及通过在耶鲁大学医学院和得克萨斯州A & M大学支付服务费用，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T2 D治疗和预防相关的长期成本节省。 公共卫生相关性：2型糖尿病和肥胖症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。这项工作可能会提供新的机制的见解，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》的一部分，这一竞争力修订将提供就业机会和安全，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