Regulation of ENaC Trafficking

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The epithelial Na channel (ENaC) forms a pathway for Na absorption in the kidney, lung, and other epithelia. In order to maintain Na homeostasis and control blood pressure, ENaC is tightly regulated to respond to conditions of Na/volume depletion and Na/volume excess. However, defects in this regulation are responsible for nearly all of the known inherited forms of hypertension, and contributes to the pathogenesis of cystic fibrosis. The overall hypothesis of the proposed research is that mechanisms that control ENaC trafficking are critical for the regulation of epithelial Na transport. We propose three Specific Aims to test this hypothesis. 1. Our previous work indicates that Nedd4-2 is critical in the regulation of ENaC surface expression; defects in this regulation cause Liddle's syndrome, an inherited form of hypertension. In this aim, we will use novel approaches to investigate the mechanisms by which Nedd4-2 regulates ENaC surface expression. 2. Recent work indicates that ENaC is activated by proteolytic cleavage of the channel. Surprisingly, we found that Liddle's syndrome mutations selectively increase surface expression of cleaved ENaC channels. This provides a novel mechanism by which Liddle's syndrome mutations might alter ENaC gating. In this aim, we will pursue the underlying molecular mechanisms. 3. The assembly of ENaC subunits into a complex is a critical step in efficient trafficking to the cell surface. Based on preliminary data, we will investigate the mechanisms by which CHIP, a co-chaperone E3 ubiquitin ligase, regulates ENaC trafficking in the biosynthetic pathway. By using powerful new approaches and by testing novel hypotheses, this work will help to explain previous data and will generate new insight into mechanisms that regulate ENaC surface expression, and hence, epithelial Na transport and Na homeostasis. This has important implications for our understanding and treatment of diseases including hypertension and cystic fibrosis.