Determinants of Insulin Mediated Glucose uptake in South Asians

南亚人胰岛素介导的葡萄糖摄取的决定因素

• 批准号: 8420522
• 负责人: THEMISTOCLES LEONARD ASSIMES
• 金额: $ 18.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420522
• 关键词: Abdomen; Accounting; Address; Adipocytes; Adipose tissue; Adult; Advisory Committees; Age; Asians; Atherosclerosis; Award; Biometry; Body fat; Cardiopulmonary; Cardiovascular system; Clinical Research; Collaborations; Complex; Development; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Epidemiology; Ethnic group; Europe; European; Exercise stress test; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genotype; Glucose; Gold; Grant; Heart; Heart Diseases; Hepatocyte; Hispanics; Hospitals; Human; Human Genetics; Inherited; Insulin; Insulin Resistance; International; Knowledge; Light; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Medicine; Mentors; Methods; Mexican; Molecular Biology; Monitor; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxygen; Pathway interactions; Physical Fitness; Physical activity; Physicians; Physiological; Plant Roots; Population; Population Sciences; Predisposition; Questionnaires; Race; Recruitment Activity; Regression Analysis; Research; Research Personnel; Research Proposals; Resources; Risk; Sampling; Scanning; Scientist; Secondary Prevention; South Asian; Stress Tests; Symptoms; Taiwan; Techniques; Testing; Tissues; United States National Institutes of Health; Universities; Visceral; Work; adverse outcome; base; cardiovascular disorder risk; career development; cohort; design; experience; genetic epidemiology; genome wide association study; genome-wide; glucose uptake; high risk; human subject; improved; innovation; insight; insulin sensitivity; insulin sensitizing drugs; interest; knowledge base; next generation; novel; professor; public health relevance; racial and ethnic; research study; sex; standard measure; subcutaneous; tool; trait; uptake

DESCRIPTION (provided by applicant): The purpose of this award is to provide Dr. Themistocles (Tim) Assimes, Assistant Professor of Medicine at Stanford University, the support necessary to transition him from a junior investigator to an independent physician scientist studying the genetic determinants of various human complex traits related to cardiovascular medicine. Dr. Assimes is an adult cardiologist with an advanced degree in epidemiology and biostatistics and significant experience conducting human genetic studies using existing sample sets. Career development activities focus on consolidating his expertise by 1) designing and implementing his first human subjects clinical research study involving handling of biospecimens, 2) increasing his involvement in several international genetic epidemiology collaborations, and 3) attending didactic courses to expand his knowledge base in contemporary genetics, molecular biology, advanced statistical genetics and the pathophysiology of insulin resistance (IR). An advisory committee, which includes his mentors, Drs. Thomas Quertermous and Gerald Reaven, will carefully monitor his progress towards independence. The research proposal builds on ongoing efforts in the candidate's division to identify the root causes of IR by studying South Asians, a racial/ethnic group known to be strongly predisposed to IR and its adverse consequences for unclear reasons. In this context, Specific Aim 1 proposes to quantify IR and its primary established determinants of adiposity and physical fitness in ~330 South Asians and ~100 white/Europeans using 'gold standard' measuring tools. These include an insulin suppression test to assess insulin mediated glucose uptake, DXA and abdominal MRI scans to determine total and regional body fat, pedometers to estimate current physical activity, and a symptom limited cardiopulmonary stress test to estimate maximum oxygen uptake (max VO2). A new research partnership between the non-profit South Asian Heart Center at El Camino Hospital, Mountain View, CA, and Division of Cardiovascular Medicine at Stanford University will facilitate recruitment. This aim will test the hypothesis that a predisposition to IR in South Asians is evident even after taking into account significant differences between the two racial/ethnic groups in adiposity and physical fitness not captured by more traditional methods of assessment of these variables (e.g., BMI and physical activity questionnaires). In Specific Aim 2, the candidate will perform genome wide genotyping in ~400 South Asians followed by gene/SNP set pathway analyses using innovative analytical techniques developed by collaborators at SAGE Bionetworks. The same analytical techniques will be applied to multiple other sample sets with GWAS and direct measures of IR representing 3 other race/ethnic groups including Europeans, East Asians, and Hispanics. This aim will compare and contrast pathways associated with IR across all groups and test the hypothesis that South Asians are more IR because they have inherited a relatively inefficient cellular mechanism of handling glucose compared to other racial/ethnic groups.

描述(申请人提供)：该奖项的目的是为斯坦福大学医学助理教授Themistocle(Tim)Assimes博士提供必要的支持，使他从初级研究员转变为独立的内科科学家，研究与心血管医学相关的各种人类复杂特征的基因决定因素。阿西姆斯博士是一名成人心脏病专家，拥有流行病学和生物统计学方面的高级学位，并拥有利用现有样本进行人类遗传学研究的丰富经验。职业发展活动的重点是通过以下方式巩固他的专业知识：1)设计和实施他的第一个涉及生物样本处理的人类受试者临床研究；2)更多地参与几个国际遗传流行病学合作；3)参加教学课程，以扩大他在当代遗传学、分子生物学、高级统计遗传学和胰岛素抵抗(IR)病理生理学方面的知识基础。包括他的导师托马斯·奎特莫斯博士和杰拉尔德·里文博士在内的一个顾问委员会将仔细监测他走向独立的进展。这项研究建议建立在候选人所在部门正在进行的努力的基础上，通过研究南亚人来确定IR的根本原因，南亚人是已知具有强烈IR倾向的种族/民族及其原因不明的不利后果。在此背景下，具体目标1建议使用“黄金标准”测量工具对大约330名南亚人和大约100名白人/欧洲人的IR及其主要确定的肥胖和身体健康决定因素进行量化。这些措施包括评估胰岛素介导的葡萄糖摄取的胰岛素抑制试验，确定整体和局部体脂的DXA和腹部MRI扫描，估计当前体力活动的计步器，以及估计最大摄氧量(Max VO2)的症状限制性心肺负荷试验。加州山景城El Camino医院的非营利性南亚心脏中心与斯坦福大学心血管医学部之间的一项新的研究伙伴关系将促进招聘。这一目标将检验这样一种假设，即即使在考虑到两个种族/民族在肥胖和身体健康方面的显著差异后，南亚人仍有明显的IR倾向，这些变量的更传统评估方法(例如，BMI和体力活动问卷)没有反映出来。在具体目标2中，候选人将在约400名南亚人中进行全基因组基因分型，然后使用由SAGE Bionetworks的合作者开发的创新分析技术进行基因/SNP SET路径分析。同样的分析技术将应用于其他多个样本集，其中Gwas和直接测量IR代表其他3个种族/民族群体，包括欧洲人、东亚人和拉美裔人。这一目标将比较和对比所有群体中与IR相关的途径，并检验南亚人更具IR的假设，因为与其他种族/民族相比，他们遗传了一种相对低效的细胞机制来处理葡萄糖。