? The goal of this PPG is to test specific hypotheses of how genes within four discrete regions of Chr 13 initiate the cascade of events determining blood presure salt-sensitivity and renal dysfunction in the Dahl S (SS) rat; and to identify specific genetic polymorphisms in two of these regions that determine blood pressure, salt-sensitivity, renal damage, and vascular angiogenesis. We have demonstrated that introgression of small regions of Chr 13 from the inbred Brown Norway (BN) strain of rat into the genomic background of the SS rat strain (consomic SS-13BN) substantially reduced salt-induced hypertension and restored angiogenic capacity to the SS rat. Four of 26 overlapping SS.BN congenic strains within Chr 13 containing BN substitutions (congenic strains 1,5,9, and 26) have been selected based on their protective actions on salt-induced hypertension and vascular angiogenesis effects. We propose three closely inter-related scientific projects that bring together a team of uniquely qualified geneticists and physiologists. Project by Cowley will determine the sequential physiological and gene expression changes in response to salt intake upon the kidney, adrenal gland, and vasculature. Since sex differences affected the degree of protection from salt-induced hypertension in several of the congenic strains, one of these strains (strain 9) has been selected to determine variations of genomic and physiological pathways that may explain these differences. Project by Roman focuses on a region of Chr 13 congenic strain 5 to identify the specific gene that """"""""protects"""""""" from salt-induced hypertension in both male and female rats. Project by Greene focuses on Chr 13 congenic strain 9, to characterize the mutation that regulates the renin gene and thereby impacts upon angiotensin II formation and angiogenesis. Validation of differentially expressed and/or candidate genes will be tested using rat transgenic apporaches for Projects by Roman and Greene. The four Cores that will provide support for the PPG include: A) Administrative Core; B) Genomics Core; C) Transgenics Core; D) Research Services Core. ?
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