Genes regulating EnaC function in salt-sensitive hypertension

本实验室的主要目标是确定产生盐敏感性高血压的分子机制。拟议研究中使用的模型是达尔盐敏感(S)和耐盐(R)菌株。这些菌株具有肾处理钠的机制，参与血压升高的发病机制。提出的研究利用了先前的观察结果，即Dahl S大鼠的内髓收集管细胞在过滤器上培养时，运输的Na量是Dahl R大鼠的两倍。拟议的实验将结合这种制备与DNA微阵列分析和表达筛选，以解决以下目标。首先，鉴定培养的髓内集管中差异表达的基因，并将其定位到大鼠染色体上。其次，利用卵母细胞表达系统筛选差异表达基因，确定其是否改变Na转运，并进一步表征其作用通道机制。那些确实改变钠转运的将进一步表征和确定其作用机制。最后，在哺乳动物细胞模型中，差异表达和影响卵母细胞Na电流的基因将会过度或不足表达。这些实验将利用SCOR程序的其他组成部分，将候选基因整合到模型中，以便更好地理解钠通道和血压调节的机制。这一信息将极大地加速确定盐敏感性高血压的分子原因的进展，从而导致识别、治疗和预防策略的改进。

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.