Identifying Chromosome 3 Blood Pressure QTL Candidates

描述(申请人提供)：我们的长期目标是识别使动物对血压敏感或耐盐的基因，最终目标是将这一知识应用于阐明影响人类血压的因素。我们先前在近交系的S(Dahl)盐敏感(Dahl)和耐盐(R)大鼠的分离群体中发现了与血压相关的大鼠3号染色体上的两个基因座(RNO_3)。其中一个血压数量性状基因座(QTL)位于RNO_3的Q-末端附近，已被培育出一个同源菌株S.R-Edn3所证实。来自S.R-Edn3的同源亚株表明，在RNO_3的Q-末端至少存在两个不同的BP QTL，并将QTL的区域限定为3.3 cM。我们建议更好地定义这一QTL区间的范围，这将有助于识别控制这一BP QTL的基因(S)。我们推测至少有三个不同的BP/心脏质量QTL存在于RNO_3上，S.R-Edn3同源大鼠携带两个不同RNO_3 BP QTL的低BP等位基因，该区域R-鼠源性基因(S)表达的差异是该同源菌株血压降低的部分原因。我们的具体目标是：1)开发S.R-Edn3同源亚株，在R-大鼠RNO_3的较小部分中携带BP QTL，并最终将该区域缩小到1.0 cM；2)在D3Wox3附近的RNO_3上培育出捕获第三个BP QTL的同源菌株，该QTL距离位于Q端附近的两个BP QTL超过90 cM。R-鼠染色体的这一区域将被导入S品系。3)利用细菌人工染色体(BAC)和P1人工染色体(PAC)的重叠群，建立含有特定AIM 1中确定的BP QTL的RNO 3区域的详细遗传、比较和物理图谱；4)确定RNO 3 BP QTL的强候选基因，并将包含在QTL区域内的基因作为候选基因进行评估。我们还将利用基因芯片杂交技术，与亲本S株相比，寻找在同源亚株中差异表达的基因。定位于QTL区域的差异表达基因(在特定的AIM 1中确定)将是该特定血压QTL的更好的候选基因。

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.