ETHANOL MEDIATED CILIA MOTILITY DYSFUNCTION

乙醇介导的纤毛运动功能障碍

• 批准号: 6554468
• 负责人: Joseph H Sisson
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6554468
• 关键词: biological signal transduction; cilium /flagellum motility; enzyme activity; ethanol; laboratory rat; nitric oxide; phosphoproteins; phosphorylation; protein kinase; respiratory airway clearance; respiratory disorder; respiratory epithelium; respiratory function; toxicology

DESCRIPTION (Adapted from the applicant's abstract): Alcoholics have a high incidence of pulmonary diseases due to altered lung host defenses. A major airway defense function that is impaired during alcohol ingestion is mucociliary clearance, which is dependent on the coordinated beating of cilia that line the airways. Studies from this laboratory indicate that short term ethanol exposure stimulates ciliary motility through a nitric oxide-dependent mechanism that requires the activation of both cAMP- and cGMP-dependent protein kinases (PKA and PKG). In contrast, chronic exposure to ethanol causes desensitization of ciliary motility such that the cell no longer responds to stimulation by beta-agonists. In this context we hypothesize that: Chronic ethanol exposure impairs airway ciliary responsiveness by downregulating NO-dependent protein kinase activity resulting in altered phosphorylation of cilia target proteins and impaired mucociliary clearance. The test this hypothesis experiments will befocused around four specific aims: 1) Characterize the differences in airway cell signal transduction between acute ethanol cilia stimulation and chronic ethanol cilia desensitization; 2) Determine the intracellular factor(s) that ethanol targets resulting in chronic ciliary desensitization; 3) Determine the phosphorylation targets in the cilia axoneme that ethanol mediates through protein kinase activation; and 4) Characterize the effects in vivo of acute and chronic ethanol exposure on airway kinase activation and ciliary responsiveness. The impact of alcohol-related respiratory illnesses on society is great. The studies outlined in this proposal will explore a novel nitric oxide/PKA/PKG-dependent mechanism by which ethanol impairs ciliary function. Establishing how ethanol both acutely stimulates and chronically desensitized ciliary motility in the airway epithelium will provide meaningful insight into the role alcohol ingestion plays in the pathogenesis of bronchitis, pneumonia and lung cancer.

描述(改编自申请者的摘要)：酗酒者有一种兴奋 肺宿主防御系统改变引起的肺部疾病的发生率。一位少校 在酒精摄入过程中受损的呼吸道防御功能是 粘液纤毛清除，这依赖于纤毛的协调跳动 那排成一排的飞机。该实验室的研究表明，短期内 乙醇暴露通过一氧化氮依赖刺激纤毛运动 需要同时激活cAMP和cGMP依赖蛋白的机制 蛋白激酶(PKA和PKG)。相比之下，长期接触乙醇会导致 纤毛运动的脱敏，使细胞不再对 β-激动剂的刺激作用。在这种情况下，我们假设：慢性 酒精暴露通过下调气道纤毛反应性而损害气道纤毛反应性 NO依赖的蛋白激酶活性导致蛋白磷酸化的改变 纤毛目标蛋白和粘液纤毛清除受损。这个测试 假设实验将围绕四个具体目标展开：1) 急性呼吸道细胞信号转导的差异 乙醇纤毛刺激和慢性乙醇纤毛脱敏； 确定乙醇导致慢性阻塞性肺疾病的细胞内因子(S) 纤毛脱敏；3)纤毛中磷酸化靶标的测定 乙醇通过蛋白激酶激活介导的轴丝；和4) 刻画急性和慢性酒精暴露对小鼠的影响 气道激活剂和纤毛反应性。网络的影响 与酒精有关的呼吸道疾病对社会的影响很大。概述的研究 在这项提案中，将探索一种新的一氧化氮/PKA/PKG依赖机制 酒精会损害睫毛功能。确定乙醇是如何 急性刺激和慢性脱敏的呼吸道纤毛运动 上皮细胞将为酒精摄入的作用提供有意义的见解 在支气管炎、肺炎和肺癌的发病机制中发挥作用。