This Program Project is targeted to the genetics of hypertension in the spontaneously hypertensive rat (SHR). A central focus is on a new discrete Mendelian heart rate phenotype identified in the SHR and elicited by a mild stressor. The allele for this phenotype appears linked to a major hypertension locus and provides a new approach to identify hypertension genes. All the Research Units coordinate their attack on the goal of finding the genetic basis of hypertension in the SHR. Studies are planned to further characterize the discrete Mendelian phenotype and to map the allele in the rat genome, to probe the site and basis of a central cholinergic deficit in the SHR which permits the phenotypic expression, to identify polymorphic markers in recombinant progeny from a Brown NorwayxSHR cross and apply these findings to the SHR, to probe the genetic basis of hypersympathoadrenal activity in the SHR and relationship to the new phenotype, to characterize the phenotype of the thiazide receptor in SHR and correlate receptor expression with genetic hypertension and the mechanisms thereof, to extend studies of cardiovascular receptor mechanisms regulating gene expression via transcription factors and signal transduction pathways, to examine the role of transcription factors in regulating atrial natriuretic factor expression in cardiac myocytes by growth factors, angiotensin ad hypertrophy and to extend studies of renal adrenergic receptors and signal transduction mechanisms to understand post-receptor events in genetic models of hypertension, especially the SHR. Three Cores will support the programmatic efforts. In addition to an Administrative Core, a Breeder and Physiology Core will continue to supply highly inbred SHR and normotensive Wistar-Kyoto (WKY) rats, progeny from SHRxWKY crosses as well as progeny from the recombinant Brown NorwayxSHR cross. A Molecular Genetics Core will assist in testing polymorphic markers for their informative content in the SHR and maintain genetic quality control of bred rats. The molecular Genetics Core also contains a Genetics Unit which will advise, analyze, and interpret genetics results obtained in the animal studies as well as assist in the linkage and mapping of quantitative trait loci in the SHR from the Brown NorwayxSHR and SHRxWKY intercrosses.
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