Identifying Chromosome 3 Blood Pressure QTL Candidates

描述（由申请人提供）：我们的长期目标是鉴定使动物易患血压盐敏感性或耐盐性的基因，最终目标是将这些知识应用于阐明影响人类血压的因素。我们以前确定了两个基因座的大鼠3号染色体（RNO 3）与血压的分离人口繁殖的近交达尔盐敏感（S）和耐盐（R）的大鼠。这些血压（BP）的数量性状位点（QTL），位于RNO 3的q-末端附近，证实了开发一个同源株，S. R-Edn 3。R-Edn 3的同源亚系表明，RNO 3的q端至少存在两个不同的BP QTL，并将QTL定位区域限定在3.3cM的范围内。我们建议更好地定义这个QTL包含区间的程度，这将有助于确定基因（S）负责这个BP QTL。我们假设这些是存在于RNO 3上的至少三个不同的BP/心脏质量QTL，并且S. R-Edn 3同类大鼠携带两个不同的RNO 3 BP QTL的低BP等位基因，并且该区域中R大鼠衍生基因的表达差异部分地负责该同类品系观察到的血压降低。1）开发来源于S. R-Edn 3的同源亚系，其在R-大鼠来源的RNO 3的较小部分中携带BP QTL，并最终将该区域缩小至1.0cM; 2）培育出“捕获”RNO 3上D3 Wox 3附近的第三个BP QTL的同源株系，该QTL距离位于q端附近的两个BP QTL超过90 cM。R-大鼠染色体的该区域将渗入S品系。3)使用细菌人工染色体（BAC）和P1人工染色体（PAC）的重叠群，开发包含在SPECIFIC AIM 1中鉴定的BP QTL的RNO 3区域的详细遗传、比较和物理图谱; 4）鉴定RNO 3 BP QTL的强候选基因，并且将位于包含QTL的区域内的基因作为候选基因进行评估。我们还将通过使用cDNA阵列杂交技术，与亲本S株相比，鉴定同源亚株中差异表达的基因。定位在含有QTL的区域中的差异表达基因（在SPECIFIC AIM 1中鉴定）将是该特定血压QTL的上级候选基因。

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.