ENDOTHELIN-3--EFFECTS ON BLOOD PRESSURE AND HEART WEIGHT

这个实验室的主要兴趣是识别和 血压和心脏调节基因座的特征 肥大。我们的策略是在大鼠模型中识别这些基因座 遗传性高血压，关注近交系Dahl大鼠血液模型 耐压力、耐盐性和耐盐性。内皮素类是 已知的最有效的血管活性底物，也影响细胞生长 以及细胞外基质的产生。我们最近确认了 大麦自交系ET-3等位基因的多态分析 盐敏感(SS/JR)和耐盐(SR/JR)大鼠，我们已经将 ET-3基因座对高血压患者血压和心脏相对重量的影响 分离群体，来源于SS.JR大鼠与SR/JR的交配 以高盐饮食喂养的大鼠。绘制了ET-3基因座图 到老鼠的3号染色体，那里没有以前与血液相关的基因座 压力或相对心脏重量。我们的主要目标是确定 影响相对心脏重量的大鼠ET-3基因突变 以及血压对盐敏感和/或耐盐性。这些 突变可能影响1)蛋白质编码序列，2) 调控mRNA转录的序列，或3)调控序列 SS/JR和SR/JR大鼠的mRNA选择性剪接。第一 将通过克隆和测序编码区来解决这一可能性 ET-3等位基因。第二和第三种可能性是 SS/JR和SR/JR大鼠ET-3基因组克隆的序列分析 和基于逆转录-聚合酶链式反应(RT-PCR)的 化验。如果受调控的，而不是编码的序列出现分化， 将检测循环ET-3水平和组织ET-3 mRNBA的表达 在含有SR/JR-大鼠ET-3基因的SS/JR、SR/JR和SS/JR同源基因大鼠中。 本项目还将研究遗传背景对ET-3的影响 基因表达及该3号染色体基因座对血液的影响 近交系Dahl大鼠的血压和心肌肥厚。这个项目将 进一步了解ET-3基因的结构和调控。识别 突变导致ET-3表达的菌株差异可能有助于我们 更好地理解心肌肥厚和心肌梗死的机制 高血压。

The major interest of this laboratory is the identification and characterization of loci regulating blood pressure and cardiac hypertrophy. Our strategy is to identify these loci in rat models of genetic hypertension, focusing on the inbred Dahl rat models of blood pressure salt-sensitivity and -resistance. Endothelins are among the most potent vasoactive substrates known and also influence cell growth and the production of extracellular matrix. We have recently identified polymorphisms at the ET-3 locus distinguishing alleles in inbred Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats, We have linked the ET-3 locus to blood pressure and relative heart weight in a segregating population, derived from matings of SS.Jr rats with SR/Jr rats, that were raised on a high salt diet. The ET-3 locus was mapped to rat chromosome 3, where no loci were previously linked to blood pressure or relative heart weight. Our major goal is to identify mutations in the rat ET-3 gene that contribute to relative heart weight and blood pressure salt-sensitivity and/or salt resistance. These mutations could affect either 1) the protein-coding sequences, 2) sequences regulating mRNA transcription, or 3) sequences regulating alternative splicing of mRNA in SS/Jr and SR/Jr rats. The first possibility will be addressed by cloning and sequencing the coding region of the ET-3 alleles. The second and third possibilities will be addressed by sequence analysis of SS/Jr and SR/Jr rat ET-3 genomic clones and a Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR)-based assay. If regulatory, rather than coding, sequences appear divergent, circulating ET-3 levels and tissue ET-3 mRNBA expression will be examined in SS/Jr, SR/Jr, and congenic SS/Jr rats containing SR/Jr-rat ET-3 locus. This project will also examine the effects of genetic background on ET-3 gene expression, and the effects of this chromosome 3 locus on blood pressure and cardiac hypertrophy in inbred Dahl rats. This project will further the knowledge of ET-3 gene structure and regulation. Identifying mutations causing strain differences in ET-3 expression could help us better understand the mechanism underlying both cardiac hypertrophy and hypertension.