The goal of Project by Cowley is to use physiological and gene microarray expression data to determine how genes within four discrete regions of Chromosome 13 (Chr 13) initiate and/or maintain the cascade of events determining blood pressure salt-sensitivity and renal dysfunction in the Dahl S (SS) rat. As shown previously, introgression of the entire Chr 13 from the inbred Brown Norway (BN) strain of rat into the genomic background of the SS rat strain (consomic SS-13BN) substantially reduces salt-induced hypertension and proteinuria. We have now completed development of and have phenotyped 23 congenic inbred strains with overlapping BN Chr 13 chromosomal segments introgressed into SS. Four discrete congenic regions of these BN substitutions within the SS genomic background (congenic strains 1, 5, 9 and 26), that range in size from 4.5 to 16 Mbp resulted in significant protection from salt-induced hypertension in female rats. Reductions of the levels of hypertension ranged from 22 to 32 mmHg among these congenic strains. In addition, since sex differences affected the degree of protection from salt-induced hypertension in several of the .congenic strains, one of these strains (congenic strain 9) was selected to determine variations of genomic and physiological pathways that may explain these male and-female differences. We hypothesize that genes within these four congenic regions of Chr 13 collectively contribute to genome-wide responses and operate through shared functional pathways to improve the sodium excretory function of the kidney and thereby protect the organism from salt-induced hypertension. Three systems important in the regulation of sodium homeostasis and arterial pressure regulation will be assessed, the kidneys (cortex and medulla), the adrenals (reflecting autonomic and endocrine function) and the vasculature. Studies in Aim I will determine the sequential physiological changes in pathways under conditions of 0.4% salt diet and at 16 hr, 3 and 12 days after switching to a 4.0% salt diet.
Aim 2 will utilize gene microarrays as a powerful assay system to identify pathways and networks that are linked to whole system physiology. Molecular profiles reflected by mRNA expression will be combined with physiological profiles obtained in Aim 1 in an integrative'analysis to identify the molecular patterns and pathways that underlie common physiological systems responsible for the phenotypic differences .between the SS rat and'the reduced salt-sensitivity of the congenic strains. >Even if little is currently known of the function of a differentially expressed gene, gene function can be reverse engineered by placing .them into the context of an overall functional pathway to predict gene-function relationships. The use of congenic strains within Chr 13 with well-defined blood pressure phenotypes provides a unique opportunity to produce an integrated picture of how genes within four discrete regions of Chr 13 modify salt-induced hypertension. This may provide valuable clues to define these critical pathways responsible for salt-induced forms of hypertension in human subjects, especially in high risk populations such as African-Americans.
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