Ethanol-mediated cilia motility dysfunction

乙醇介导的纤毛运动功能障碍

• 批准号: 8135127
• 负责人: Joseph H Sisson
• 金额: $ 8万
• 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 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135127
• 关键词: Affect; Agonist; Alcohol consumption; Alcohols; Breathing; Bronchitis; Cell physiology; Chronic; Cilia; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Defect; Down-Regulation; Dynein ATPase; Enzymes; Epithelial; Epithelium; Ethanol; Excision; Functional disorder; Funding; Health; Host Defense; Impairment; In Vitro; Individual; Infection; Injury; Isoproterenol; Knowledge; Learning; Lung; Mediating; Modeling; Molecular; Motor; Mucociliary Clearance; Mucous body substance; Mus; Nitric Oxide; Organelles; Phosphorylation; Phosphotransferases; Play; Pneumonia; Production; Protein Kinase; Proteins; Pulmonary aspiration of gastric contents; Rattus; Regulation; Research Personnel; Respiratory physiology; Risk; Role; Signal Pathway; Speed; Stress; Structure; Time; Upper Respiratory Infections; airway epithelium; airway inflammation; alcohol exposure; base; cell motility; cilium motility; desensitization; design; feeding; fighting; genetic regulatory protein; in vivo; injured; microorganism; oxidant stress; particle; prevent; programs; protein kinase A kinase; research study

DESCRIPTION (provided by applicant): Heavy alcohol intake is known to damage the ability of the lung to protect itself from infections such as pneumonia and bronchitis. The lung's first line of defense against such infection is to trap inhaled particles and propel them out of the lung using the mucociliary apparatus. In a healthy individual, this apparatus produces mucus, which traps inhaled particles, and is then propelled out of the lung by cilia, the fingerlike projections of the lung lining. Damage to cilia results in pneumonia and loss of lung function. We have established that alcohol profoundly injures this delicate mucociliary apparatus by altering critical proteins called kinases. Two of these kinases, PKA and PKG, are well-described molecules that regulate cell functions including lung cilia. Our experiments in alcohol-fed mice have demonstrated that alcohol profoundly impairs the function of these kinases, resulting in a loss of the normal "fight or flight" responsiveness of the mucociliary apparatus in a manner that requires the production of nitric oxide. While we have established that alcohol causes this problem, we do not know how long it persists if alcohol is removed. We also do not know exactly how alcohol alters these important kinase-dependent functions in cilia. This leads us to hypothesize that: Chronic alcohol exposure causes time-dependent and reversible impairment of mucociliary function by altering specific regulatory proteins in airway epithelial cilia. In this proposal, we propose experiments designed to answer two questions: 1. Is alcohol-driven impairment of mucociliary function preventable or reversible? and 2. Which cilia proteins are affected by alcohol? We propose to answer these questions through experiments proposed in four specific aims: 1. Characterize the time course and reversibility of chronic alcohol impairment of mucociliary function; 2. Define the signaling pathways and role that oxidant stress plays in alcohol-mediated nitric oxide-dependent regulation of ciliary motility, 3. Determine the kinase phosphorylation targets present on cilia that are altered by alcohol exposure; and 4. Identify the molecular determinants of alcohol-mediated cilia injury using isolated cilia models. Although we have learned much about the impact and mechanisms of alcohol injury to mucociliary function, the studies we propose will extend our knowledge into how this may be prevented or treated and exactly how alcohol alters molecules critical for cilia function and lung health.

描述（由申请人提供）：已知重酒精摄入会损害肺部免受肺炎和支气管炎等感染的能力。肺部针对这种感染的第一道防线是使用粘膜纤毛装置将吸入颗粒捕获并将其驱逐出肺。在一个健康的个体中，该设备会产生粘液，从而捕获吸入的颗粒，然后被Cilia从肺中推出，这是肺衬里的指形斑点。纤毛损害导致肺炎和肺功能丧失。我们已经确定，酒精通过改变称为激酶的临界蛋白质来深深地伤害这种细腻的粘膜固定仪。这些激酶中的两个，PKA和PKG是良好描述的分子，可调节包括肺纤毛在内的细胞功能。我们在酒精喂养小鼠中的实验表明，酒精会严重损害这些激酶的功能，从而损失了粘膜纤毛仪的正常“战斗或飞行”反应性，需要一种需要产生一氧化氮的方式。尽管我们确定酒精会导致这个问题，但我们不知道如果去除酒精，它会持续多长时间。我们也不确切地知道酒精如何改变纤毛中这些重要的激酶依赖性功能。这导致我们假设：长期的酒精暴露会通过改变气道上皮纤毛中的特定调节蛋白而导致时间依赖性和可逆性损伤。在此提案中，我们提出了旨在回答两个问题的实验：1。酒精驱动的粘膜屈光功能是否可以预防或可逆？和2。哪种纤毛蛋白受到酒精的影响？我们建议通过提出的四个具体目的提出的实验回答这些问题：1。表征慢性酒精功能的时间过程和可逆性； 2。定义氧化应激在酒精介导的一氧化氮依赖性调节中的信号传导途径和作用，3。确定纤毛中存在的激酶磷酸化靶标会因酒精暴露而改变。和4。使用分离的纤毛模型确定酒精介导的纤毛损伤的分子决定因素。尽管我们已经了解了酒精损伤对粘膜函数的影响和机制的知识，但我们提出的研究将扩展到可以预防或治疗的知识，以及酒精如何改变对纤毛功能和肺部健康至关重要的分子。