Role of Mucin in Lung Homeostasis and Pathophysiology

粘蛋白在肺稳态和病理生理学中的作用

• 批准号: 8316176
• 负责人: Christopher M Evans
• 金额: $ 38.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316176
• 关键词: Accounting; Achievement; Animal Disease Models; Asthma; Autopsy; Breathing; Cell Culture Techniques; Cells; Chronic Obstructive Airway Disease; Cystic Fibrosis; Development; Distal; Epithelial Cells; Exocytosis; Functional disorder; Genetically Engineered Mouse; Glycoproteins; Goals; Health; Histologic; Homeostasis; Human; Knockout Mice; Lung; Lung diseases; MUC5AC gene; MUC5B gene; Mechanics; Mediating; Morbidity - disease rate; Mucins; Mucous body substance; Mus; Nature; Obstruction; Obstructive Lung Diseases; Pathway interactions; Patients; Play; Production; Proteins; Respiratory physiology; Role; Site; Sputum; Testing; Thick; X-Ray Computed Tomography; airway hyperresponsiveness; antigen challenge; base; in vivo; insight; methacholine; mortality; novel; research study; respiratory

DESCRIPTION (provided by applicant): Mucus hypersecretion and airway hyperreactivity (AHR) are significant features of asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). In spite of these well-recognized pathological associations, the mechanisms by which AHR is mediated by the chief glycoprotein components of respiratory mucus, the secreted polymeric mucins, are unknown. Autopsy studies show that 98% of the airways of patients who die from fatal asthma have extensive mucus plugging. MUC5AC and MUC5B are the major secreted airway mucins. Their production (especially that of MUC5AC) increases significantly in asthma, CF, and COPD, and in animal models of these diseases. Furthermore, blockade of mucus secretion reduces AHR by ~80%. These findings provide the basis for the overall goal of this proposal, which is to assess the functional consequences of mucus secretion on lung function. The central hypothesis of this proposal is that secreted Muc5ac and Muc5b play essential roles in the development of airway hyperreactivity by promoting mucus thickening, airway lumen occlusion, and distal airway closure. Studies will be conducted in human airway epithelial cell cultures and knockout mice in order to achieve the following specific aims: Aim 1: Determine the role of polymeric mucin secretion in mucus layer thickening. Aim 2: Determine the functional consequences of polymeric mucin secretion on AHR. PUBLIC HEALTH RELEVANCE: Mucus overproduction and hypersecretion are cardinal features that are strongly associated with morbidity and mortality in asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Our studies are aimed at understanding how mucus is secreted, how it is altered in lung disease, and what the functional consequences of these are, using genetically engineered mice and cells grown in culture. Achievement of these goals will provide insights into novel treatments of obstructive lung diseases.

描述（由申请人提供）：粘液分泌过多和气道高反应性（AHR）是哮喘、囊性纤维化（CF）和慢性阻塞性肺病（COPD）的显着特征。尽管存在这些众所周知的病理关联，但呼吸道粘液的主要糖蛋白成分（分泌的聚合粘蛋白）介导 AHR 的机制尚不清楚。尸检研究表明，98% 死于致命性哮喘的患者气道有广泛的粘液堵塞。 MUC5AC 和MUC5B 是主要的分泌性气道粘蛋白。它们的产生（尤其是 MUC5AC）在哮喘、CF 和 COPD 以及这些疾病的动物模型中显着增加。此外，粘液分泌的阻断可使 AHR 降低约 80%。这些发现为该提案的总体目标提供了基础，即评估粘液分泌对肺功能的功能影响。该提议的中心假设是，分泌的 Muc5ac 和 Muc5b 通过促进粘液增厚、气道腔闭塞和远端气道闭合，在气道高反应性的发展中发挥重要作用。将在人气道上皮细胞培养物和基因敲除小鼠中进行研究，以实现以下具体目标： 目标 1：确定聚合粘蛋白分泌在粘液层增厚中的作用。目标 2：确定聚合粘蛋白分泌对 AHR 的功能影响。公共卫生相关性：粘液产生过多和分泌过多是与哮喘、囊性纤维化 (CF) 和慢性阻塞性肺病 (COPD) 的发病率和死亡率密切相关的主要特征。我们的研究旨在利用基因工程小鼠和培养细胞来了解粘液是如何分泌的，它在肺部疾病中是如何改变的，以及这些功能的后果是什么。这些目标的实现将为阻塞性肺病的新疗法提供见解。