BLOOD PRESSURE CANDIDATE GENE SCREENING--A NEW PARADIGM

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DESCRIPTION: (Adapted from the Investigator's Abstract) The essential mechanisms (and the genes underlying them) leading to hypertension need identification for better understanding and treatment of this complex disorder. The most direct way of accomplishing this is to identify genes regulating blood pressure in animal models of genetic hypertension. The applicants have linked loci on rat chromosomes 3 and 7 to blood pressure quantitative trait loci (BP QTL) in a segregating population bred from inbred Dahl salt-sensitive (S) and salt-resistant (R) rats fed a high salt diet. Introgression of R-rat derived chromosomal regions containing these two QTLs into S rats resulted in congenic strains with significantly lower blood pressure and cardiac mass compared to S rats, confirming the presence of BP QTL in the introgressed regions of chromosomes 3 and 7. Similar methodology has been used by others to develop congenic strains carrying BP QTLs located on six other chromosomes, resulting in a panel of eight congenic strains derived from the Dahl rat model of blood pressure salt-sensitivity. The applicant hypothesizes that gene(s) underlying a given BP QTL may be differentially expressed in target organs/tissues. If so, such a gene should also be differentially regulated in congenic strains carrying different BP QTL. Gene(s) responsible for a QTL's effect should show a congenic strain-specific differential-pattern of expression in a target organ(s) and should map to the chromosomal interval carried by that particular congenic strain. Therefore, genes having such characteristics will be superior candidates as genes responsible for, at least in part, a specific BP QTL. The applicant proposes to identify candidate genes for BP QTL as follows: Differentially expressed genes will be identified in the kidneys of S and R rats, on both low NaCl (genetic-differences) and high NaCl diets (salt-responsive). Renal RNA expression of such differentially-expressed genes will be examined in a panel of congenic strains carrying Dahl rat BP QTL, where each strain carries a low blood pressure allele for a different BP QTL on a background of S-rat alleles. Genes having a congenic strain-specific pattern of differential gene expression will be mapped to determine their genomic location. Genes with a 1) congenic strain-specific pattern of differential gene expression and 2) mapping to the introgressed chromosomal region containing a specific BP QTL, will be considered strong candidates for the gene(s) responsible for blood pressure differences associated with this QTL. This new approach should accelerate the identification of strong candidate genes for particular BP QTL and, potentially, of new blood pressure regulatory mechanisms.