Identifying Chromosome 3 Blood Pressure QTL Candidates

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DESCRIPTION (provided by applicant): Our long-term goal is to identify genes pre-disposing animals to blood pressure salt-sensitivity or salt-resistance, with the eventual goal of applying this knowledge to elucidating factors influencing blood pressure in humans. We previously identified two loci on rat chromosome 3 (RNO3) linked to blood pressure in a segregating population bred from inbred Dahl salt-sensitive (S) and salt-resistant (R) rats. One of these blood pressure (BP) quantitative trait loci (QTL), located near the q-terminus of RNO3, was confirmed by developing a congenic strain, S.R-Edn3. Congenic substrains derived from S.R-Edn3 indicated that at least two distinct BP QTLs are present at the q-terminus of RNO3 and delimited the QTL-containing region to 3.3 cM interval. We propose to better define this QTL-containing interval's extent, which will assist in identifying gene(s) responsible for this BP QTL. We hypothesize that these are at least three distinct BP/cardiac mass QTLs present on RNO3 and that the S.R-Edn3 congenic rat carries low BP alleles for two distinct RNO3 BP QTL and that differences in the expression of R-rat derived gene(s) in this region are responsible, in part, for this congenic strain's observed decreased blood pressure.Our SPECIFIC AIMS are to: 1) develop congenic substrains derived from S.R-Edn3, that carry the BP QTLs in smaller portions of the R-rat derived RNO3 and eventually narrowing this region to 1.0 cM; 2) develop congenic strains "trapping" the third BP QTL present on RNO3 near D3Wox3, which maps over 90 cM away from the two BP QTL located near the q-terminus. This region of R-rat chromosome will be introgressed into the S strain. 3) develop detailed genetic, comparative, and physical maps of the RNO3 region containing the BP QTL identified in SPECIFIC AIM 1 using contigs of bacterial artificial chromosomes (BAC) and P1 artificial chromosomes (PAC); 4) identify strong candidate genes for the RNO3 BP QTL, and genes located within the QTL-containing regions will be evaluated as candidates. We will also identify genes differentially-expressed in congenic substrains, compared with the parental S strain, by using the cDNA array hybridization technique. Differentially-expressed genes that map in the QTL-containing region (identified in SPECIFIC AIM 1) will be superior candidate genes for that specific blood pressure QTL.