ETHANOL MEDIATED CILIA MOTILITY DYSFUNCTION

乙醇介导的纤毛运动功能障碍

• 批准号: 6196778
• 负责人: Joseph H Sisson
• 金额: $ 33.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6196778
• 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（改编自申请人的摘要）：酗酒者有很高的 由于肺部宿主防御改变而导致的肺部疾病的发病率。一个主要 在酒精摄入过程中受损的气道防御功能， 粘膜纤毛清除，这取决于纤毛的协调跳动 排列在呼吸道上该实验室的研究表明， 乙醇暴露通过一氧化氮依赖性的 需要激活cAMP和cGMP依赖性蛋白的机制 激酶（PKA和PKG）。相反，长期接触乙醇会导致 纤毛运动的脱敏，使得细胞不再响应于 β-受体激动剂的刺激。在这种情况下，我们假设： 乙醇暴露通过下调气道纤毛反应性 一氧化氮依赖性蛋白激酶活性导致 纤毛靶蛋白和受损的粘膜纤毛清除。这个测试 假设实验将围绕四个具体目标：1） 表征急性和慢性哮喘患者之间气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; 2） 确定乙醇靶向导致慢性炎症的细胞内因子 纤毛脱敏; 3）确定纤毛中的磷酸化靶点 乙醇通过蛋白激酶活化介导的轴丝;和4） 描述急性和慢性乙醇暴露对 气道激酶激活和纤毛反应性。的影响 与酒精有关的呼吸道疾病对社会的影响是巨大的。研究概述 本研究将探索一种新的一氧化氮/PKA/PKG依赖性机制 乙醇通过其损害纤毛功能。确定乙醇如何既 急性刺激和慢性脱敏纤毛运动的气道 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起作用。