Trafficking and Regulation of the Epithelial Na+ Channel

描述(申请人提供)：维持细胞外液容量的动态平衡对于血流动力学的稳定和肾脏的异常是必不可少的。 钠的摄入与心血管疾病和高血压有关。 肾脏钠排泄的最终调节发生在远端。 肾单位通过阿米洛利敏感上皮钠的传导转运 频道(ENaC)。ENAC在人牙周炎根尖膜中的表达和活性 上皮细胞是钠重吸收的限速步骤，不仅在 肾脏集合管，但也存在于呼吸道上皮和结肠。 ENaC功能异常表现为遗传性 高血压、肾脏盐耗和囊性纤维化。的长期目标是 本研究旨在了解调控ENaC基因表达的因素。 上皮细胞的顶膜以及激素、 生理条件和其他途径(如囊性纤维化 跨膜调节器)控制ENaC功能。实验将定义 合成、顶端表达、内吞、循环和降解 极化良好的肾细胞中的ENAC亚单位。然后我们将研究一部小说 解释基础状态下ENaC亚单位非协调调节的范式 以及我们和其他研究人员所拥有的激素刺激条件 观察到的。

DESCRIPTION (provided by applicant): Maintenance of extracellular fluid volume homeostasis is essential for hemodynamic stability, and abnormalities of renal sodium handling have been linked to cardiovascular disease and hypertension. Ultimate regulation of sodium excretion in the kidney occurs in the distal nephron via conductive transport through the amiloride sensitive epithelial Na+ channel (ENaC). ENaC expression and activity in the apical membrane of epithelial cells is the rate limiting step in Na+ reabsorption not only in kidney collecting duct, but in airway epithelia and colon as well. Abnormalities of ENaC function have been demonstrated in hereditary forms of hypertension, renal salt wasting, and cystic fibrosis. The long term goal of this research is to understand the factors that regulate ENaC expression in the apical membrane of epithelial cells and the mechanisms by which hormones, physiologic conditions and other channels (such as the cystic fibrosis transmembrane regulator, CFTR) control ENaC function. Experiments will define the synthesis, apical expression, endocytosis, recycling and degradation of ENaC subunits in well polarized kidney cells. We will then examine a novel paradigm to explain the non-coordinate regulation of ENaC subunits under basal and hormonally-stimulated conditions that we and other investigators have observed.