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：
7743824
负责人：
JOHN P. JOHNSON
金额：
$ 23.63万
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：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743824
关键词：
Apical Basic Science Binding Biochemical Cardiovascular Diseases Cell Line Cells Cellular Membrane Clathrin Clathrin Adaptors Clathrin-Coated Vesicles Cleaved cell Colon 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 Epithelial Cells Epitopes Equilibrium Essential Hypertension Excision Excretory function Extracellular Fluid Fibrosis 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 Pathologic Pathway interactions Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Physiological Play Polyubiquitination Population Probability Process Protein Synthesis Inhibition Proteins Proteolysis 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 overexpression research study salt sensitive trafficking wasting

项目摘要

PROVIDED. . Maintenance of.extracellular fluid volume homeostasis is essential for hemodynamic stability, and abnormalities of renal sodiumhandlinghave 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 amiloridesensitive 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. Abnormalitiesof 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 controlof 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 channelto the membrane, retrieval through endocytosis, and the balance between recyclingand degradation of the channel. Multiple observations in responsive cell lines and native tissues including kidney and lung have demonstratedthat modulation of channel activity is associated with non-coordinate regulation of the three separate subunits whichmake up the fully active channel. The current experiments will define the binding partners and regulatory sites ofclathrin- mediated endocytosis of the channel,the fate of the individual subunits within the endocytic pathways and the regulation of channel recyclingto the apical membrane. Experiments are designed to determine if non-coordinate regulation of channel subunits takes place in the endocytic pathwayand 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. ¿ ¿

假如。。维持。细胞液体体积稳态对于血液动力学稳定性至关重要，异常肾脏钠handlinghave与心血管疾病和高血压有关，钠的最终调节肾脏中的排泄通过通过淀粉样上皮的导电转运在远端肾单位发生 Na+通道（ENAC）。上皮细胞的顶膜中的ENAC表达和活性是速率限制步骤在Na+中，不仅在肾脏收集到应得的肾脏，而且在气道上皮和结肠中。异常 ENAC功能已在遗传形式的盐敏感性高血压，肾盐浪费和囊性中得到证明纤维化。这项研究的长期目标是了解调节顶端ENAC表达的因素上皮细胞的膜以及马，生理条件和其他通道的机制（这样作为囊性纤维化trahsmmbrane调节剂CFTR）控制ENAC函数。 ENAC功能的主要控制功能是；通过调节Na+重吸收细胞膜中的活动通道数量的调节。频道是被蛋白水解裂解激活。控制通道的顶端表达的控制是Channelto的传递的函数膜，通过内吞作用的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，已经证明通道活动的调节与三个单独亚基的非坐标调节有关向上完全活跃的通道。当前的实验将定义诊断蛋白的结合伙伴和调节位点介导的通道内吞作用，内吞途径内各个亚基的命运和调节对顶膜的通道回收利用。实验旨在确定是否非坐标通道亚基的调节发生在内吞途径中，与野生类型的差异处理有关和裂解的通道，这些通道被蛋白水解激活。该研究旨在确定监管机制在高血压等疾病状态下，这可能受到异常调节。 »