Determinants of Insulin Mediated Glucose uptake in South Asians

描述（由申请人提供）：本奖项的目的是为斯坦福大学医学助理教授Themistocles (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遗传决定因素。Assimes博士是一名成人心脏病专家，拥有流行病学和生物统计学高级学位，并具有使用现有样本集进行人类基因研究的丰富经验。职业发展活动的重点是巩固他的专业知识：1)设计和实施他的第一个涉及生物标本处理的人类受试者临床研究，2)增加他在几个国际遗传流行病学合作中的参与，以及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。一个咨询委员会，包括他的导师，博士。托马斯·奎尔特莫斯和杰拉尔德·雷文，会仔细监督他走向独立的进程。该研究计划建立在候选人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，南亚人是一个已知易患IR的种族/民族群体，其不良后果的原因尚不清楚。在此背景下，具体目标1建议使用“金标准”测量工具，量化约330名南亚人和约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。其中包括胰岛素抑制试验以评估胰岛素介导的葡萄糖摄取，DXA和腹部MRI扫描以确定总和局部体脂，计步器以估计当前的身体活动，以及症状限制性心肺应激试验以估计最大摄氧量（最大VO2）。位于加州山景城埃尔卡米诺医院的非营利性南亚心脏中心和斯坦福大学心血管医学部之间的一项新的研究合作将促进招聘。这一目的将检验这样一个假设，即即使考虑到两个种族/民族在肥胖和身体健康方面的显著差异，南亚人的IR易感性也是明显的，而传统的评估这些变量的方法（例如，BMI和身体活动问卷）没有捕捉到这些差异。在Specific Aim 2中，候选人将对约400名南亚人进行全基因组基因分型，然后使用SAGE Bionetworks的合作者开发的创新分析技术进行基因/SNP集通路分析。同样的分析技术将应用于多个其他样本集，其中包括GWAS和代表其他3个种族/民族的IR直接测量，包括欧洲人、东亚人和西班牙人。这一目标将比较和对比所有群体中与IR相关的途径，并验证南亚人IR更高的假设，因为与其他种族/民族相比，他们遗传了相对低效的细胞处理葡萄糖机制。

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. PUBLIC HEALTH RELEVANCE: Insulin resistance is a physiologic state where fat, muscle and liver cells lose their ability to respond to insulin. The resulting high levels of insulin predispose to the development of diabetes, heart disease, and other serious conditions. Work proposed in this grant aims to identify the reasons some populations are particularly high risk of insulin resistance and its consequences.