Genes regulating EnaC function in salt-sensitive hypertension

盐敏感性高血压中 EnaC 功能调节基因

• 批准号: 6843762
• 负责人: JOHN B STOKES
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843762
• 关键词: Xenopus oocyte; angiotensin /renin /aldosterone hypertension; corticosteroids; disease /disorder etiology; disease /disorder model; enzyme mechanism; epithelium; expression cloning; familial hypertension; genetic library; genetic mapping; genetic regulation; genetic strain; hormone regulation /control mechanism; hypertension; in situ hybridization; ion transport; laboratory rat; microarray technology; molecular genetics; molecular pathology; renal tubular transport; sodium channel; tissue /cell culture

The major goal of this laboratory is to identify the molecular mechanisms responsible for producing for producing salt-sensitive hypertension. The models used for the proposed studies are the Dahl salt-sensitive (S) and salt resistant (R) strains. These strains have renal mechanisms of Na handling that participate in the pathogenesis of elevated blood pressure. The proposed studies take advantage of previous observations that the inner medullary collecting duct cells of Dahl S rats, when cultured on filters, transport twice as much Na as those of the Dahl R rat. The proposed experiments will combine this preparation with DNA microarray analysis and expression screening to address the following aims. First, differentially expressed genes in the cultured inner medullary collecting ducts will be identified and localized on the rat chromosome. Second, differentially expressed genes will be screened using the oocyte expression system to determine if they alter Na transport will be further characterized and their mechanism of action channel. Those that do alter Na transport will be further characterized and their mechanism of action ascertained. Finally, genes that are differentially expressed and affect Na currents in oocytes will be over- or under-expressed in mammalian cell models. The experiments will be design to take advantage of other components of this SCOR program to integrate candidate genes into models where the mechanisms of Na channel and blood pressure regulation can be better understood. This information should greatly accelerate the progress toward identifying the molecular causes of salt- sensitive hypertension and thus lead to improved strategies for identification, treatment, and prevention.

该实验室的主要目标是确定负责产生盐敏感高血压的分子机制。用于拟议研究的模型是DAHL盐敏感（S）和耐盐（R）菌株。这些菌株具有参与血压升高的发病机理的NA处理的肾脏机制。拟议的研究利用了先前的观察结果，即在过滤器上培养的Dahl s大鼠的内髓质收集管细胞的运输是Dahl R大鼠的两倍。提出的实验将将这种制剂与DNA微阵列分析和表达筛选结合在一起，以解决以下目的。首先，将在大鼠染色体上鉴定并定位在培养的内髓质收集管中差异表达的基因。其次，将使用卵母细胞表达系统筛选差异表达的基因，以确定它们是否会进一步表征Na转运和其作用通道机理。那些确实改变了NA运输的人将得到进一步的特征，并确定其作用机理。最后，在哺乳动物细胞模型中差异表达并影响卵母细胞中Na电流的基因将过度表达。实验将是设计来利用该SCOR计划的其他组成部分，以将候选基因整合到模型中，在这些模型中，可以更好地理解NA通道和血压调节的机制。这些信息应大大加速识别盐敏感高血压的分子原因的进展，从而改善鉴定，治疗和预防的策略。