The overall goal of this project is to further insight into the genetic basis of salt-sensitive hypertension in genetically hypertensive rats. We will evaluate the role of intermediate physiologic phenotypes as genetic contributors to salt-sensitive hypertension in Dahl rats, spontaneously hypertensive rats (SHR), and borderline hypertensive rats (BHR). There is substantial evidence from both human hypertension and genetic hypertension in rats that complex quantitative traits such as alterations in sympathetic neural function and vascular structure contribute importantly to the pathogenesis of spontaneous hypertension, but there have been few studies addressing this concept using modern genetic approaches.
Our aims i s to test the hypotheses that: l - altered sympathetic neural mechanisms are a genetic determinant of salt-induced hypertension in Dahl salt- sensitive(S) rats, SHR and BHR, and 2. arteriolar remodeling in the form of a reduction in external vessel diameter distinct from hypertrophy is a genetic determinant of hypertension in Dahl S rats and SHR. To test these hypotheses, we will 1 - employ segregating populations from crosses of the genetically hypertensive and normotensive rats to determine if the putative intermediate neural and vascular structural phenotypes cosegregate with blood pressure, and 2. use genetic markers to identify chromosomal quantitative trait loci(QTLs) Nhat Co segregate with these intermediate neural and structural phenotypes. We will also capitalize - on the availability of congenic strains of Dahl rats that differ only in a segment of chromosome containing either the """"""""r"""""""" or """"""""s"""""""" allele for 11B- hydroxylase to test the concept that genetic variation in 11B-hydroxylase gene and steroid production in S and R acts in the central nervous system to alter sympathetic neural regulation and arterial pressure in Dahl rats. The studies in this project are close intertwined with Dr. Rapp's work in Project 3 aimed at identifying QTLs that influence blood pressure in the Dahl rat. Our work is aimed at advancing insight into the physiologic intermediate phenotypes that may be regulated by QTLs exerting a major influence on blood pressure in Dahl rats.
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