AGING AND HYPERTENSION--GENDER, GENES AND RISK

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DESCRIPTION: (Adapted from applicant's abstract). This application is for a Mentored Clinical Scientist Development Award. The applicant states that that sexual dimorphisms in cardiovascular risk evolve with increasing age, and that women experience significantly less hypertension and heart disease than do men -- though this difference disappears with increasing age, especially among Blacks. The research plan in this proposal aims to pursue preliminary evidence which suggests that age, gender and race play a key role in modifying the ultimate expression of genetic risk. In particular, preliminary data reveal that females are protected against expression of a common intermediate phenotype of essential hypertension, marked by abnormal responsiveness to angiotensin II. And among the many genes proposed to cause human hypertension, one of the very few for which linkage has been documented is that coding for angiotensinogen (AGT), a key element of the renin-angiotensin system - yet linkage has been convincingly shown only in males. The present proposal aims to test the hypothesis that the ultimate expression of the AGT gene is strongly influenced by age, gender, and hormonal status. It will test whether female hormone replacement therapy (HRT) can confer the same protection as do endogenous sex steroid hormones; whether race influences the relationship between AGT genotype and the phenotype of AngII responsiveness; and whether nutritional factors, ultimately involving obesity, contribute. With anticipated award the applicant's plan is to continue clinical research in hypertension, applying techniques and understanding of renal and adrenal physiology to the process of aging. Controlled physiologic studies by her will be performed on the Clinical Research Center of the Brigham and Women's Hospital. As well, she will be mentored by Dr. Lewis Lipsitz who is experienced in cardiovascular function and disease in the aging populations. The applicant's stated goal is to establish for herself an independent research career path for studying cardiovascular, renal, and adrenal function in relation to the pathogenesis of hypertension in the elderly.