Y Chromosome Genes and Essential Hypertension in American Males

主要研究者的职业发展计划和目标 博士Ikhide Imumorin在德克萨斯A&M大学接受动物遗传学培训，并开始研究人类遗传学 作为内分泌学，糖尿病和营养学系的博士后研究员， 来自马里兰州医学院，巴尔的摩（Pis：Alan Shuldiner和布拉克斯顿Mitchell）。这份拨款申请 将使他能够在遗传学高级研究人员的指导下发展他的研究技能， 心血管疾病他的主要目标是利用这个RIMI子奖，以增加他的研究 通过逐步提高他对遗传学的兴趣的速度和生产力， 原发性高血压（EH）的流行病学。该奖项将使伊莫林博士（i）产生和 在一个发育良好的高血压大鼠模型中验证初步数据;（ii）在一个表征良好的 人类群体和（iii）对选定Y染色体进行遗传关联分析 染色体基因与人类高血压预计他将过渡到非RIMI来源 五年期结束时的外部支助。由于很少有人知道男性特有的作用， Y（MSY）基因在EH中的作用，本建议拟展开一项长期研究计划，了解 MSY基因如何影响EH，以及MSY基因如何与其他常染色体基因相互作用， 与绝经前女性相比，男性中EH的明显性二态患病率。在 在随后的研究中，他希望（i）进行MSY基因的大规模表达分析，（ii）获得 关于MSY在各种雄性器官和组织中表达的蛋白质的体内和体外数据，（iii）进行大规模的 MSY基因变异的规模鉴定和验证，（iv）检查MSY的基因-基因相互作用， 涉及交感神经系统，脂质代谢， 钠摄入和排泄、社会压力和与睾酮作用的相互作用以及（v）检查MSY 基因-环境相互作用，如环境应激源和血液中涉及的药理学 在人类病例对照和基于家庭的关联分析框架内的压力调节。 研究项目和增进对少数民族健康差异的了解 据NIH称，人们普遍认为，有许多疾病和障碍， 不成比例地影响美国种族和少数民族人口的健康。显然 非裔美国人、西班牙裔美国人、美洲印第安人、阿拉斯加原住民、一些亚裔美国人， 和其他太平洋岛民经历更高的风险和健康状况比一般 人口在少数群体中，原发性高血压是一种不成比例的疾病。国家卫生研究院 其使命是更好地了解这种健康差异的遗传和环境基础 并减少因卫生保健和健康结果不公平而造成的人力和经济成本。 该项目的提出是为了利用NHLBI资助的一项大型多种族研究-- 动脉粥样硬化的多种族研究（梅萨）项目，以了解动脉粥样硬化以及种族和 种族差异可能会导致死亡率和发病率。我们的项目将能够进入一口井 在美国四个主要种族/民族背景的特征研究人群，并将增加我们的 了解Y染色体上的基因是如何与大鼠（Sry）有明显联系的 可能与种族/民族相互作用，以推动这种健康差距。私家侦探组织了一个 在心血管疾病遗传学领域具有60多年经验的合格研究者， 人和大鼠高血压模型进行这项研究。

Career Developmental Plans and Objectives of Principal Investigator Dr. Ikhide Imumorin trained in animal genetics at Texas A&M University and got a start in human genetics as a Postdoctoral Research Fellow in the Division of Endocrinology, Diabetes and Nutrition at the University of Maryland School of Medicine, Baltimore (Pis: Alan Shuldiner and Braxton Mitchell). This grant proposal will enable him to develop his research skills under the mentorship of senior investigators in the genetics of cardiovascular disease. His primary goal is to utilize this RIMI sub-award to increase his research competitiveness by progressively enhancing the pace and productivity of his interests in the genetic epidemiology of essential hypertension (EH). This award will enable Dr. Imumorin to (i) generate and validate preliminary data in a well-developed hypertensive rat model; (ii) test the results in a wellcharacterized human population and (iii) conduct genetic association analysis of selected Y chromosome genes and human hypertension. It is expected that he will transition to non-RIMI sources of external support at the end of the 5-year period. Since very little is known about the role of male-specific Y (MSY) genes in EH, this proposal intends to launch a long-term research program to understand how MSY genes influence EH and how MSY genes interact with other autosomal genes to cause the apparent sexually dimorphic prevalence of EH in males compared to pre-menopausal females. In subsequent studies, he hopes to (i) conduct large scale expression analyses of MSY genes, (ii) obtain //?- vivo and in-vitro data on MSY expressed proteins in various male organs and tissues, (iii) undertake large scale identification and validation of MSY gene variants, (iv) examine gene-gene interactions of MSY and autosomal loci in multiple pathways involving genes of the sympathetic nervous system, lipid metabolism, sodium intake and excretion, social stress and interaction with testosterone action and (v) examine MSY gene-environment interactions such as environmental stressors and pharmacologies implicated in blood pressure regulation within the framework of case-control and family based association analyses in humans. Research Project and Advancing Understanding of Health Disparities in Minorities According to the NIH, it is widely recognized that there are many diseases and disorders that disproportionately affect the health of racial and ethnic minority populations in the United States. It is evident that African-Americans, Hispanic Americans, American Indians, Alaska Natives, some Asian-Americans, and other Pacific Islanders experience much higher risks and poorer health status than the general population. Among the diseases that disproportionately afflict minorities is essential hypertension. The NIH has a mission to better understand the genetic and environmental underpinnings of this disparity in health and to reduce the human and economic costs resulting from inequities in health care and health outcomes. This project has been proposed to take advantage of a large multi-ethnic study funded by the NHLBI - the Multi Ethnic Study of Atherosclerosis (MESA) project to understand atherosclerosis and how racial and ethnic differences may contribute to mortality and morbidity. Our project will be able to access a well characterized study population of four major racial/ethnic backgrounds in the U.S. and will increase our understanding of how genes on the Y chromosome one of which has been clearly implicated in rat (Sry) may interact with race/ethnicity to drive this health disparity. The PI has assembled a team of highly qualified investigators with a combined experience of over 60 years in genetics of cardiovascular disease in both human and the rat model of hypertension to undertake this study.