Epithelial Sodium Channel Trafficking

上皮钠通道贩运

• 批准号: 8435710
• 负责人: Peter M Snyder
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435710
• 关键词: Acetylation; Aldosterone; Attention; Back; Cardiovascular Diseases; Cell surface; Cells; Complex; Cystic Fibrosis; Defect; Degradation Pathway; Development; Disease; Endocytosis; Endocytosis Pathway; Endosomes; Epithelial; Epithelium; Equilibrium; Face; Goals; Homeostasis; Hydrolase; Hypertension; Individual; Inherited; Ion Channel; Kidney; Knowledge; Lung; Lysine; Maintenance; Mediating; Molecular; Mus; Mutation; Myocardial Infarction; Pathogenesis; Pathway interactions; Phosphorylation; Play; Population; Process; Recycling; Regulation; Role; Sodium; Sodium Channel; Sorting - Cell Movement; Stroke; Surface; Syndrome; Testing; Ubiquitin; Ubiquitination; Vasopressins; Veterans; Work; absorption; base; blood pressure regulation; effective therapy; epithelial Na+ channel; innovation; insight; novel; prevent; public health relevance; response; stem; trafficking; ubiquitin-protein ligase; uptake

DESCRIPTION (provided by applicant): The epithelial Na+ channel (ENaC) forms a pathway for Na+ absorption in the kidney, lung, and other epithelia. ENaC is tightly regulated in order to maintain Na+ homeostasis and to control blood pressure. Defects in this regulation upset the delicate balance and cause disease. Importantly, many of the identified inherited forms of hypertension result from defects in ENaC regulation. A defect in ENaC regulation may also contribute to the pathogenesis of cystic fibrosis. Thus, our long term goal is to understand the mechanisms that regulate ENaC as a prerequisite for the development of more targeted treatments for these diseases. A convergence of recent discoveries has focused attention on ubiquitination as a critical mechanism that regulates ENaC trafficking. By reducing ENaC surface expression, ubiquitination decreases epithelial Na+ absorption, which is an important adaptive response in the face of Na+/volume excess. In this proposal, we will investigate the molecular mechanisms by which ubiquitination controls ENaC trafficking. This work capitalizes on our previous discoveries that the E3 ubiquitin ligase Nedd4-2 catalyzes ENaC ubiquitination and reduces ENaC expression at the cell surface at two distinct steps in the trafficking pathway (endocytosis and lysosomal degradation). Importantly, defects in this pathway are responsible for Liddle's syndrome. Moreover, Nedd4-2 is a critical convergence point by which aldosterone and vasopressin regulate ENaC. Although it is clear that ubiquitination plays a critically important role in the regulation of epithelial Na+ absorption, there are important gaps in our knowledge. The overall goal of this proposal is to understand the molecular mechanisms by which ubiquitination regulates ENaC, and hence, epithelial Na+ transport. We will investigate mechanisms by which E3 ubiquitin ligases regulate ENaC trafficking, investigate mechanisms that regulate ENaC sorting in endosomes, and investigate the role of lysine acetylation in ENaC trafficking. By testing novel hypotheses and using innovative approaches, this work will generate new insights into mechanisms by which ubiquitination regulates ENaC surface expression, and hence, epithelial Na+ transport and Na+ homeostasis. This may have important implications for our understanding and treatment of diseases including hypertension and cystic fibrosis.

描述（由申请人提供）： 上皮Na+通道（ENAC）形成了肾脏，肺部和其他上皮中Na+吸收的途径。为了维持NA+稳态并控制血压，ENAC受到严格调节。该法规中的缺陷破坏了微妙的平衡并导致疾病。重要的是，许多确定的遗传形式的高血压形式来自ENAC调节中的缺陷。 ENAC调节缺陷也可能有助于囊性纤维化的发病机理。因此，我们的长期目标是了解调节ENAC作为开发这些疾病更具针对性治疗的先决条件的机制。最近发现的融合将注意力集中在泛素化上，这是调节ENAC贩运的关键机制。通过降低ENAC表面表达，泛素化降低了上皮Na+吸收，这是Na+/体积过量的重要自适应反应。在此提案中，我们将研究泛素化控制ENAC贩运的分子机制。这项工作利用了我们以前的发现，即E3泛素连接酶NEDD4-2催化ENAC泛素化，并在运输途径的两个不同步骤（内吞作用和溶酶体降解）中降低细胞表面的ENAC表达。重要的是，该途径中的缺陷导致了Liddle综合征。 此外，NEDD4-2是醛固酮和加压素调节ENAC的关键收敛点。尽管很明显，泛素化在调节上皮Na+吸收中起着至关重要的作用，但我们的知识存在重要差距。该提案的总体目标是了解泛素化调节ENAC的分子机制，从而调节上皮Na+转运。我们将研究E3泛素连接酶调节ENAC运输的机制，调查调节内体中ENAC分类的机制，并研究赖氨酸乙酰化在ENAC运输中的作用。通过测试新的假设并使用创新方法，这项工作将对泛素化调节ENAC表面表达的机制产生新的见解，因此，上皮Na+转运和Na+稳态。这可能对我们对包括高血压和囊性纤维化在内的疾病的理解和治疗具有重要意义。