Role of Mucin in Lung Homeostasis and Pathophysiology

描述(申请人提供)：粘液高分泌和呼吸道高反应性(AHR)是哮喘、囊性纤维化(CF)和慢性阻塞性肺疾病(COPD)的重要特征。尽管有这些公认的病理联系，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，死于致命哮喘的患者98%的呼吸道有广泛的粘液堵塞。MUC5AC和MUC5B是主要的呼吸道分泌性粘蛋白。在哮喘、慢性阻塞性肺疾病和慢性阻塞性肺疾病以及这些疾病的动物模型中，它们的产生(特别是MUC5AC)显著增加。此外，阻断粘液分泌可使AHR降低约80%。这些发现为这项建议的总体目标提供了基础，该目标是评估粘液分泌对肺功能的功能影响。这一建议的中心假设是，分泌型MUC5Ac和MUC5B通过促进粘液增厚、气道腔阻塞和远端气道口关闭，在气道高反应性的发展中发挥重要作用。将在人呼吸道上皮细胞培养和基因敲除小鼠中进行研究，以实现以下特定目标：目的1：确定聚合粘蛋白分泌在粘液层增厚中的作用。目的2：确定多聚性粘蛋白分泌对AHR的功能影响。公共卫生相关性：粘液过度生产和高分泌是哮喘、囊性纤维化(CF)和慢性阻塞性肺疾病(COPD)的主要特征，与发病率和死亡率密切相关。我们的研究旨在了解粘液是如何分泌的，在肺部疾病中是如何改变的，以及这些变化的功能后果是什么，使用基因工程小鼠和在培养中生长的细胞。这些目标的实现将为阻塞性肺疾病的新疗法提供见解。

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.