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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：
8018190
负责人：
JOHN P. JOHNSON
金额：
$ 23.39万
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/8018190
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 Cells Epitopes Equilibrium Essential Hypertension Excision Excretory function Extracellular Fluid Goals Grant Half-Life Homeostasis Hormones Hypertension Individual Inherited Ion Channel Kidney Length Link 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 Translational Research Ubiquitin Ubiquitination Vacuolar Protein Sorting Vesicle Work airway epithelium apical membrane base coated pit design epithelial Na+ channel epsin hemodynamics 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. ¿ ¿

提供了. 维持细胞外液容量的稳态对于血流动力学的稳定是必不可少的，并且细胞外液的异常也是重要的。肾脏钠处理与心血管疾病和高血压有关，钠的最终调节肾脏中的排泄发生在远端肾单位中，通过阿米洛利敏感上皮细胞的传导转运 Na+通道（ENaC）。上皮细胞顶膜中ENaC的表达和活性是细胞凋亡的限速步骤。 Na+重吸收不仅在肾集合管中，而且在气道上皮和结肠中也是如此。异常情况 ENaC功能已在遗传性盐敏感性高血压、肾性盐耗和囊性高血压中得到证实。纤维化本研究的长期目标是了解调控根尖细胞中ENaC表达的因素，上皮细胞的膜以及激素、生理条件和其他通道（如作为囊性纤维化跨膜调节因子CFTR）控制ENaC功能。ENaC功能的主要控制是：通过调节Na+重吸收细胞膜上活性通道的数量来实现。通道由蛋白水解裂解激活。控制该通道的顶端表达是该通道递送的功能，膜，通过内吞作用回收，以及通道的回收和降解之间的平衡。在应答细胞系和天然组织（包括肾和肺）中的多次观察表明，通道活性的调节与三个独立亚基的非协调调节有关，完全激活的频道目前的实验将确定网格蛋白的结合伴侣和调控位点，通道介导的内吞作用，内吞途径内各个亚基的命运，调节顶端膜的通道再循环。实验旨在确定非协调通道亚基的调节发生在内吞途径，并与野生型的差异处理有关。和已被蛋白水解激活的裂解通道。这项研究旨在确定监管机制其在疾病状态如高血压中可能受到异常调节。¿ ¿