NEW EXPERIMENTAL MODELS OF HYPERTENSION

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DESCRIPTION (provided by the applicant): The spontaneously hypertensive rat (SHR) is the most widely studied animal model of essential hypertension and has been a valuable tool for studying the pharmacology and physiology of blood pressure control. However, despite 30 years of research with this model, the primary mechanisms responsible for hypertension in the SHR remain undefined. Recently, we have succeeded in trapping a quantitative trait locus (QTL) for hypertension within a narrow segment of chromosome 8 in a unique congenic strain of SHR. In the current studies, we will exploit this congenic strain together with proven strategies of genome wide expression analysis and meiotic mapping to identify the molecular lesion(s) responsible for the effect of this region of chromosome 8 on blood pressure. We will pursue two alternative hypotheses using complementary strategies as follows: Hypothesis 1. A hypertension gene exists within the target segment of chromosome 8 that is differentially expressed between the SHR and the SHR congenic strain in one of the major organs suspected to be involved in the primary pathogenesis of spontaneous hypertension (brain, adrenal gland, or kidney). Accordingly, we will search for candidates for hypertension within the target chromosome segment by screening for genes that are differentially expressed between these organs of the SHR and the SHR congenic strain and that map back within the congenic segment of chromosome 8. Hypothesis 2. A hypertension gene exists within the target segment of chromosome 8 that is not differentially expressed between the SHR and the SHR congenic strain. To cover for this alternative possibility, we will also narrow the location of the hypertension gene by meiotic mapping analysis of a segregating F2 population derived from the SHR progenitor strain and the SHR congenic strain that carries the target region of chromosome 8 from the BN strain. Hypertension candidate genes will then be isolated using cDNA screening techniques to identify genes expressed in the brain, adrenal gland, or kidney that map within this chromosome region.