The proposed studies examine the hypothesis that the phenotypes of blood pressure salt sensitivity, renal failure, and hyperlipidemia comprise a syndrome that is caused, in part, by closely linked genes, or genes exhibiting pleiotropy, localized to rat chromosomes 13 and 18. The goal of this project is to apply chromosomal substitution techniques (consomic and congenic inbred rat strains) to partition these traits and identify putative candidate genes based upon detailed physiological studies and expression profiling of discrete regions of these chromosomes.
Aim 1 is to determine if hypertension salt- sensitivity, hyperlipidemia, and renal dysfunction are reduced by the introgression of either Chr 13 or Chr 18 from Brown Norway rats onto the genomic background of Dahl S salt sensitive rats (consomic inbred strains). Given the modification of the trait(s) of interest, in Aim 2 ten informative congenic sublines will be developed to partition each of these chromosomes into approximately 10 cM overlapping genomic regions. Each of these sublines will be screened for the traits of interest to select the congenic strains most affected by the introgression of BN alleles. These two congenic sublines will undergo detailed studies of renal physiology and cDNA expression profiling proposed in Aim 3. The goal of these studies is to quantify the influence of genes in these narrow regions upon the physiological pathways that determine the renal pressure-natriuresis relationship such as glomerular filtration, renal cortical and medullary blood flow, tubuloglomerular feedback, and other aspects of kidney function. Finally, in Aim 4 they propose to narrow the QTL regions containing genes that influence arterial pressure salt-sensitivity, renal dysfunction and hyperlipidemia by carrying out backcrosses of the congenic substrains studied in Aim 3 to the parental Dahl salt sensitive rats. The informative recombinant rats will be selected and phenotyped in order to reduce the QTL regions to between 0.5 and 1.0 cM.
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