Trafficking and Regulation of the Epithelial Na+ Channel

上皮Na通道的运输和调节

• 批准号: 7992609
• 负责人: JOHN P. JOHNSON
• 金额: $ 10万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992609
• 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

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. ¿ ¿

但前提是。。 维持细胞外液容量的动态平衡对于血流动力学的稳定是必不可少的， 肾脏钠的使用与心血管疾病和高血压有关，钠的终极调节 肾脏的排泄发生在远端肾单位，通过阿米迪敏感上皮传导运输。 Na+通道(ENaC)。ENAC在上皮细胞顶膜中的表达和活性是限速步骤 在Na+重吸收方面，不仅在肾脏聚集诱导，而且在呼吸道上皮和结肠也是如此。异常情况 ENAC功能已在遗传性盐敏感型高血压、肾性盐耗和囊肿症中得到证实。 纤维化症。本研究的长期目标是了解调节根尖细胞ENaC表达的因素。 上皮细胞的膜以及激素、生理条件和其他途径(如 作为囊性纤维化的跨膜调节因子，CFTR控制ENaC的功能。ENaC功能的主要控制是； 通过调节Na+重吸收细胞膜上的活性通道数而发挥作用。频道有 被蛋白水解性裂解激活。通道顶端表达的控制是通道To传递的函数 膜，通过内吞作用恢复，以及通道的循环和降解之间的平衡。 对反应细胞系和包括肾脏和肺在内的自然组织的多项观察表明， 通道活动的调制与三个单独的亚单位的非协调调节有关，这使得 在完全活跃的频道上。目前的实验将定义clathrin的结合伙伴和调控位点- 介导的内吞作用，内吞通路中各个亚基的命运和 通道循环对根尖膜的调节作用。实验的目的是确定非坐标 通道亚单位的调节发生在胞内途径中，并与野生型的差异处理有关 以及被蛋白水解酶激活的裂解通道。这项研究旨在确定监管机制 在高血压等疾病状态下，它可能会受到异常调节。？