This proposal comprises five scientific projects and two supporting core units that investigate various aspects of the genetics, pathogenesis and vascular complications of clinical and experimental hypertension. Project I will assemble a roster of multigenerational families and sibships affected by hypertension or hypotension, whose members will be subgrouped into relatively homogeneous intermediate phenotypes according to a number of biological traits. Their data will become part of a computerized database and their DNA will be used to study candidate genes and to screen chromosomal regions for linkage and association with hypertension or hypotension. Project II will use quantitative loci mapping techniques to identify genes involved in hypertension or hypotension in inbred mouse strains. Close interaction and continuous exchange between these two projects will ensure that promising fmdings in mice will be used to target homologous regions in human chromosomes and vice-versa. Project lll will explore the interaction of hypertension and hypercholesterolemia in initiating cellular and molecular mechanisms leading to atherogenesis and cardiac injury, and the effects of antihypertensives in preventing this damage, using transgenic and knockout mouse models with selective alterations in receptors or response genes. Project IV will explore the role of alpha2-adrenergic receptor subtypes in blood pressure regulation. Transgenic knockout mice will be utilized to determine the role of each of the three alpha2-adrenergic receptor subtypes in normotension and hypertension. Simultaneously, the mechanisms of alpha2-adrenergic receptor gene expression and regulation will be investigated in the transgenic models and in cell culture systems. Project V will develop and apply a number of innovative techniques for parallel processing and coincident detection to allow more efficient analysis of large humbers of samples for microsatellite markers, candidate sequences and cDNA's from selected genomic regions. Using these techniques, the investigators will search for differences in genomic DNA between normotensive and hypertensive subjects and for differences in cDNA profiling in blood and endothelial cell lines and other tissues from hypertensive humans and animals. The SCOR includes an animal core and an administrative core unit.
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