Identifying Chromosome 3 Blood Pressure QTL Candidates

鉴定 3 号染色体血压 QTL 候选者

• 批准号: 6970869
• 负责人: GEORGE T CICILA
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-16 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970869
• 关键词: angiotensin /renin /aldosterone hypertension; animal breeding; essential hypertension; genetic mapping; genetic strain; genetic susceptibility; hypertension; inbreeding; laboratory rat; microarray technology; quantitative trait loci

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.

描述（由申请人提供）：我们的长期目标是识别使动物对血压盐敏感或抗盐的基因，最终目标是将这些知识应用于阐明影响人类血压的因素。我们之前在近交 Dahl 盐敏感 (S) 和耐盐 (R) 大鼠中培育出的隔离群体中，在大鼠 3 号染色体 (RNO3) 上发现了两个与血压相关的位点。这些血压 (BP) 数量性状位点 (QTL) 之一位于 RNO3 的 q 末端附近，通过开发同源菌株 S.R-Edn3 得到证实。源自S.R-Edn3的同源亚系表明，RNO3的q末端至少存在两个不同的BP QTL，并将包含QTL的区域界定为3.3 cM间隔。我们建议更好地定义这个包含 QTL 的区间范围，这将有助于识别负责这个 BP QTL 的基因。我们假设这些是 RNO3 上存在的至少三个不同的 BP/心脏质量 QTL，并且 S.R-Edn3 同类大鼠携带两个不同的 RNO3 BP QTL 的低血压等位基因，并且该区域中 R-大鼠衍生基因的表达差异部分是导致该同类品系观察到的血压降低的部分原因。我们的具体目标是：1) 开发同类亚系 源自S.R-Edn3，其在R-rat衍生的RNO3的较小部分中携带BP QTL，并最终将该区域缩小至1.0 cM； 2) 开发同源菌株“捕获”D3Wox3 附近 RNO3 上存在的第三个 BP QTL，该 QTL 与位于 q 末端附近的两个 BP QTL 相距超过 90 cM。 R-大鼠染色体的该区域将渗入到S品系中。 3) 使用细菌人工染色体 (BAC) 和 P1 人工染色体 (PAC) 的重叠群，绘制包含 SPECIFIC AIM 1 中鉴定的 BP QTL 的 RNO3 区域的详细遗传、比较和物理图谱； 4) 识别RNO3 BP QTL的强候选基因，并且位于包含QTL的区域内的基因将被评估为候选基因。我们还将通过使用 cDNA 阵列杂交技术来鉴定与亲本 S 菌株相比，同源亚菌株中差异表达的基因。定位在包含 QTL 的区域（在 SPECIFIC AIM 1 中鉴定）中的差异表达基因将是该特定血压 QTL 的优质候选基因。