The goal of Project 3 is to locate """"""""hypertensive"""""""" loci using a large (>300) F2 cross derived from normotensive Brown Norway and Dahl salt- sensitive hypertensive rats. The F2 progeny will be extensively phenotyped after exposure to a high salt diet. In addition to salt- sensitivity, the Dahl S model of hypertension shares many similarities with phenotypic traits associated with hypertension in African Americans including insulin resistance, hyperlipidemia, and rapid development of severe progressive-hypertensive glomerulosclerosis that leads to end- stage renal disease. The F2 progeny will be genotyped using a total genomic search strategy and a candidate gene approach for determination of loci that cosegregate with arterial pressure and hypertension related phenotypes which correspond to those studied in the human populations on Projects 1 and 2 (e.g. vascular reactivity, renal function, and hyperlipidemia). QTLs which cosegregate with blood pressure or hypertension related phenotypes will be converted to homologous regions in the human and then be used to screen our patient populations. Once a region or regions are identified which cosegregate with salt-sensitive hypertension, we propose to enhance the localization of the blood pressure regulatory genes by creating new strains of rats that are identical except for selected regions of a single chromosome (congenic lines). These rats will then enable us to study the physiological mechanisms by which these loci influence blood pressure.
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