Trafficking and Regulation of the Epithelial Na+ Channel

上皮Na通道的运输和调节

基本信息

批准号：
7212758
负责人：
JOHN P. JOHNSON
金额：
$ 26.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7212758
关键词：
Amiloride Apical Basic Science Binding Biochemical Cardiovascular Diseases Cell Line Cells Cellular Membrane Clathrin Clathrin Adaptors Clathrin-Coated Vesicles Cleaved cell Colon Condition Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Defect Deubiquitinating Enzyme Deubiquitination Disease Distal Dominant-Negative Mutation Down-Regulation Duct (organ) structure Dynamin Early Endosome Endocytosis Epithelial Cells Epitopes Equilibrium Essential Hypertension Excision Excretory function Extracellular Fluid Genus Cola Goals Grant Half-Life Homeostasis Hormones Hypertension Individual Inherited Ion Channel Kidney Length Link Liquid substance Lung MDCK cell Maintenance Mediating Membrane Membrane Microdomains Molecular Mono-S Nephrons Numbers Pathologic Pathway interactions Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Physiological Play Polyubiquitination Population Probability Process Protein Overexpression Protein Synthesis Inhibition Proteins Proteolysis Rate Recruitment Activity Recycling Regulation Relative (related person)Renal Hypertension Research Retrieval Role Site Sodium Sodium Chloride Sorting - Cell Movement Structure Syndrome Techniques Testing Tissues Ubiquitin Ubiquitination Vacuolar Protein Sorting Vesicle Work airway epithelium apical membrane base coated pit design epithelial Na+ channel epsin hemodynamics hepatocyte growth factor-regulated tyrosine kinase substrate inhibitor/antagonist mutant research study salt sensitive trafficking wasting

项目摘要

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 the kidney collecting duce, but in airway epithelia and colon as well. Abnormalities of ENaC function have been demonstrated in hereditary forms of salt-sensitive 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 trahsmembrane regulator CFTR) control ENaC function. Major control of ENaC function is exerted by regulation of the number of active channels in the membrane of Na+ reabsorbing cells. Channels are activated by proteolytic cleavage. Control of apical expression of the channel is a function of delivery of the channel to the membrane, retrieval through endocytosis, and the balance between recycling and degradation of the channel. Multiple observations in responsive cell lines and native tissues including kidney and lung have demonstrated that modulation of channel activity is associated with non-coordinate regulation of the 3 separate subunits which make up the fully active channel. The current experiments will define the binding partners and regulatory sites of clathrin-mediated endocytosis of the channel, the fate of the individual subunits within the endocytic pathways and the regulation of channel recycling to the apical membrane. Experiments are designed to determine if non-coordinate regulation of channel subunits takes place in the endocytic pathway and is related to differential handling of wild type and cleaved channels which have.been activated by proteolysis. The research aims to identify regulatory mechanisms which may be subject to abnormal regulation in disease states such as hypertension.

描述（由申请人提供）：维持。细胞流体体积体积稳态对于血流动力学稳定性至关重要，肾脏钠处理的异常与心血管疾病和高血压有关，高血压和高血压，最终调节肾脏在Nephron的肾脏中通过Ambitial sistemilial sistimilialirilesimirielidiessimentiment septiS nephron中的肾脏排泄。上皮细胞的顶膜中的ENAC表达和活性是Na+重吸收的速率限制步骤，不仅在肾脏收集duce中，而且在气道上皮和结肠中也是如此。 ENAC功能的异常已在遗传形式的盐敏感性高血压，肾脏盐浪费和囊性纤维化中得到证明。这项研究的长期目标是了解调节上皮细胞顶膜中的ENAC表达的因素，以及激素，生理条件和其他通道（例如囊性纤维化TRAHSMMMMBRANE调节剂CFTR）控制ENAC功能的机制。通过调节Na+重吸收细胞的膜中活性通道的数量来施加ENAC功能的主要控制。通道通过蛋白水解裂解激活。控制通道的顶端表达是将通道传递到膜的函数，通过内吞作用检索以及通道的回收和降解之间的平衡。在响应式细胞系和包括肾脏和肺在内的天然组织中进行了多次观察表明，通道活性的调节与构成完全活跃通道的3个单独的亚基的非坐标调节有关。当前的实验将定义网格蛋白介导的通道内吞作用的结合伴侣和调节位点，内吞途径内各个亚基的命运以及对顶膜的通道回收的调节。实验旨在确定通道亚基的非坐标调节是否发生在内吞途径中，并且与野生型和裂解通道的差异处理有关。通过蛋白水解激活。该研究旨在确定在高血压等疾病状态中可能受到异常调节的调节机制。