Y Chromosome Genes and Essential Hypertension in American Males

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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.