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

该实验室的主要兴趣是鉴定和 调节血压和心脏的位点的表征 肥厚 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，重点是近交系达尔大鼠模型的血液 压盐敏感性和抗盐性。 内皮素是 已知最有效的血管活性底物，也影响细胞生长 和细胞外基质的产生。 我们最近发现 ET-3位点的多态性在近交系Dahl中区分等位基因 盐敏感（SS/Jr）和盐抗性（SR/Jr）大鼠，我们已经联系 ET-3位点与血压和相对心脏重量关系 分离群体，来源于SS.Jr大鼠与SR/Jr大鼠的交配 高盐饮食饲养的老鼠。 ET-3基因座定位 老鼠的3号染色体上，以前没有基因座与血液有关， 压力或相对心脏重量。 我们的主要目标是确定 导致相对心脏重量的大鼠ET-3基因突变 以及血压盐敏感性和/或盐抗性。 这些 突变可能会影响1）蛋白质编码序列，2） 调节mRNA转录的序列，或3）调节 在SS/Jr和SR/Jr大鼠中mRNA的选择性剪接。 第一 通过克隆和测序编码区， ET-3等位基因 第二和第三种可能性是 通过SS/Jr和SR/Jr大鼠ET-3基因组克隆的序列分析解决 和基于逆转录酶-聚合酶链式反应（RT-PCR）的 比色法 如果调控序列而不是编码序列出现分歧， 将检查循环ET-3水平和组织ET-3 mRNBA表达 在SS/Jr、SR/Jr和含SR/Jr大鼠ET-3基因座的同系SS/Jr大鼠中。 本项目还将研究遗传背景对ET-3的影响 基因表达，以及3号染色体对血液的影响 压力和心脏肥大的关系。 该项目将 进一步了解ET-3基因的结构和调控。 识别 导致ET-3表达的菌株差异的突变可以帮助我们 更好地了解心肌肥大和 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.