Regulation of ENaC by Proteases and SGK1

蛋白酶和 SGK1 对 ENaC 的调节

• 批准号: 7215375
• 负责人: Monroe JACKSON Stutts
• 金额: $ 40.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215375
• 关键词: Acute; Address; Affect; Air; Apical; Breathing; CAP1; Cell membrane; Cell physiology; Cell surface; Cells; Chemicals; Condition; Data; Depth; Disease; Endopeptidases; Environment; Epithelial; Epithelial Cells; Epithelium; Failure; Film; Gases; Health; Height; Human; In Vitro; Knowledge; Leukocyte Elastase; Link; Liquid substance; Lung; Lung diseases; Measures; Mediating; Mission; Modeling; Molecular; Nucleotides; Numbers; Other Agency or Organization; Particulate; Pathway interactions; Patients; Peptide Hydrolases; Physiological Processes; Population; Probability; Process; Protease Inhibitor; Pseudohypoaldosteronism; Public Health; Pulmonary Cystic Fibrosis; Rate; Regulation; Regulation of Proteolysis; Relative (related person); Research; Respiratory physiology; Role; Serine Protease; Signal Transduction; Sodium Chloride; Stimulus; Surface; Testing; Work; absorption; airway epithelium; airway surface liquid; apical membrane; base; cystic fibrosis patients; density; design; epithelial Na+ channel; extracellular; human PRSS8 protein; in vivo; mouse model; particle; pathogen; respiratory; response

Project II, "Regulation of ENaC by Proteases and SGK1", has as its long-term objective the better understanding of the molecular mechanisms that link the rate of Na+ absorption by airway epithelia to physical conditions on the airway surface. Relevance to the mission of the agency is that the airway surface is the largest interface between the body and the outside environment, and the airway must continuously rid its surface of inhaled particulates. To do so, it has strongly conserved processes for regulating the height of the thin film of liquid on its surface. Excessive Na+ absorption mediated by airway epithelial Na+ channels (ENaC) contributes to lung disease in cystic fibrosis patients, but the mechanisms that normally restrain ENaC are poorly defined. To better understand how respiratory pathogens and/or inhaled chemicals could upset normal regulation in the airways, we propose to examine the regulation of ENaC by two pathways that may link the rate of Na+ absorption to stimuli present on the airway surface. The Project has thee aims. Aim 1: Extracellular proteolytic activity, as either soluble proteases, such as neutrophil elastase, or endogenous surface proteases, probably CAP1 (prostasin), stimulate near silent Po approx. 0.01) ENaC to become active (Po approx 0.5). Protease inhibitors, though essential for the model, are not addressed in this Project, which focuses on the molecular mechanism of proteolytic regulation. Aim 2: The role of ENaC surface density and turnover in airway health and disease is unknown. Aim 2 tests the effects of SGK1, ATP, and proteases on ENaC surface density and turnover. Aim 3 explores protease regulation of airway surface liquid volume in highly differentiated human airway cells in vitro and in a mouse model, in vivo. Our studies are focused on the effects of local signals on the open probability and surface density of ENaC, and how these modes of regulating Na+ transport satisfy the airway's requirement for tonic volume absorption, while preserving its ability to accelerate or slow the process as conditions on the airway surface require. Relevance to Public Health: This research is designed to study the physiologic processes responsible for clearing inhaled particles from the surface of the airways, so that the airways are able to deliver fresh air to the lungs' gas exchange surface.

项目第二，“蛋白酶和SGK1对ENAC的调节”的长期目标越好 理解将气道上皮亚吸收速率的分子机制与 气道表面的身体状况。与该机构的任务相关的是气道表面 是身体和外部环境之间最大的界面，气道必须不断脱离 它的吸入颗粒表面。为此，它具有强烈保守的过程来调节高度 液体在其表面上的薄膜。由气道上皮Na+通道介导的过多Na+吸收 （ENAC）在囊性纤维化患者中有助于肺部疾病，但通常限制的机制 ENAC的定义很差。为了更好地了解呼吸道病原体和/或吸入化学物质如何 我们建议通过两种途径来检查ENAC的调节，这两种途径 可以将Na+吸收的速率与气道表面上存在的刺激联系起来。该项目的目标。目的 1：细胞外蛋白水解活性，例如可溶性蛋白酶，例如中性粒细胞弹性蛋白酶或内源性蛋白酶 表面蛋白酶，可能是CAP1（前列腺素），刺激接近无声的PO。 0.01）ENAC活跃 （PO大约0.5）。蛋白酶抑制剂虽然对模型必不可少，但在该项目中没有解决， 侧重于蛋白水解调节的分子机制。目标2：ENAC表面密度和 气道健康和疾病的营业额尚不清楚。 AIM 2测试SGK1，ATP和蛋白酶对 ENAC表面密度和周转。 AIM 3探索气道表面液体体积的蛋白酶调节 体外和小鼠模型中高度分化的人类气道细胞在体内。我们的研究专注于 局部信号对ENAC的开放概率和表面密度的影响，以及这些模式如何 调节Na+运输满足气道对补品量吸收的需求，同时保留其 随着气道表面上的条件需要加速或减慢过程的能力。与公众有关 健康：这项研究旨在研究负责清除吸入的生理过程 来自气道表面的颗粒，使气道能够向肺部的气体传递新鲜空气 交换表面。