The overall goal of the Hypertension SCOR (H-SCOR) is to investigate the genetic determinants responsible for the abnormalities in volume and pressure homeostasis in human hypertension. Because of our preliminary results, this program will primarily concentrate on the hormones of the renin-angiotensin and kallikrein-kinin systems, their interactions with blood pressure, the kidney and the adrenal cortex. The H-SCOR program will continue support of a 14-year collaborative program in this research area between Harvard Medical School and the University of Utah School of Medicine. To address the questions posed in this H-SCOR, we will focus on a series of linked problems in the genetics of human hypertension, employing state-of-the-art techniques to study human physiology and pathophysiology in relation to genotype. To the extent that the information from these techniques is limited, we will extend the range of knowledge in those areas by exploiting whole animal and isolated cell physiology, cell culture procedures, transgenic technology, congenic animal techniques, electrophysiology, protein chemistry, and molecular biology. In our human studies, we will use the techniques of affected sibling pair linkage analysis to identify genes responsible for some forms of human hypertension. To achieve our goal, our strategy will be to employ a series of already well-established intermediate phenotypes to subtype our hypertensive patients. We already have made substantial progress on the goals of this project. Second, we will address the genetic factors conferring susceptibility to the development of renal complications in a specific subtype of the hypertensive population in whom dysregulation of salt and water homeostasis already has been established -- patients with hypertension and diabetes mellitus. Parallel animal studies are planned to support this program by investigating abnormalities found in humans at a level currently impossible with clinical studies. Using congenic technology we have been focussing on isolating genetic factors in stroke-prone spontaneously hypertensive rats (SHR). One major genetic factor which will be the theme of one project is related to the kallikrein-kinin system. Finally, another unique feature of this program is the routine use of the 'intermediate phenotype' in both the human and animal studies to link the gene disorder to the consequent pathophysiology of the human disease. A common laboratory core to accomplish this purpose, employed by all of the projects, is a central feature in reaching that goal. Thus, both humans and animals will have a common set of physiologic and biochemical evaluations to determine whether, in the case of animal studies, the genetic alterations produce a pathophysiologic phenotype similar to what is observed in subsets of the essential hypertensive population. These projects, with their multidisciplinary and interrelated designs should provide important clues as to the underlying genetic mechanisms and, therefore, pathogenesis of essential hypertension.
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