The overall goal of the Hypertension SCOR is to investigate the genetic determinants responsible for abnormalities in volume and pressure homeostasis in human hypertension. This application will continue support of an 18-year collaborative program between Harvard Medical School and the University of Utah School of Medicine. The five projects proposed in this renewal application expand on several of the discoveries made during the past four years. To address the questions posed in this SCOR, they will focus on a series of linked problems in the genetics of human genotype. To the extent that the information from these in vivo human techniques is limited, other techniques have been used including whole animal and isolated cell physiology - termed in vitro phenotyping when human cells are used - cell culture procedures, transgenic technology, protein chemistry, and molecular biology. There are four features to this proposal. First, is the routine use of the """"""""intermediate phenotype"""""""" to subtype hypertensive patients and thereby increase the likelihood of linking the consequent pathophysiology to (a) specific gene(s). Second, while contributing to use the techniques of affected sibling pair and pedigree linkage analysis, they also will use association analysis where the """"""""controls"""""""" are the hypertensive subjects who do not have the intermediate phenotype being investigated. Third, they will identify the genes conferring susceptibility to renal complications in a specific subset of the hypertensive population in whom dysregulation of salt and water homeostasis is well known - patients with abnormalities found in humans at a level currently impossible with clinical studies. Using transgenic technology, they have developed tissue-specific expression and knock out of components of the renin-angiotensin system in the renal tubule to explore in depth the control and function of the renal tubular RAS. To the four cores currently supporting these projects (Administration, Biochemistry, Data Processing and Analysis, and Molecular Genetics) they have added a fifth (Human Phenotyping). These projects, with their multidisciplinary and interrelated designs should provide important clues as to the underlying genetic mechanisms and, therefore, pathogenesis of human hypertension.
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