Ligand-Receptor Segregation and Airway Remodeling

配体-受体分离和气道重塑

• 批准号: 6942288
• 负责人: Joseph Zabner
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-23 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942288
• 关键词: Adenoviridae; asthma; cell differentiation; cell growth regulation; clinical research; epidermal growth factor; genetically modified animals; growth factor receptors; heregulin; host organism interaction; human tissue; hyperplasia; hypertrophy; immunocytochemistry; laboratory mouse; laboratory rat; lung injury; molecular pathology; phosphorylation; protein localization; protein protein interaction; protein structure function; respiratory epithelium; virus protein

DESCRIPTION (provided by applicant): Asthma is a heterogeneous disease of the airways characterized by chronic inflammation, airway remodeling, goblet cell metaplasia/hyperplasia, increased mucus secretion and bronchial hyperresponsiveness. The airway epithelium functions primarily as a barrier, preventing access of inhaled particulate matter, viruses, and pollutants to the lung. The polarized nature of an epithelium is such that the tight junctions function to separate the apical membrane and its components from the basolateral membrane and its components. The importance of this barrier is highlighted by the novel observation provided by our preliminary data that explains how human airway epithelia can constitutively express both a mitogenic ligand (heregulin-alpha) and its receptors (erbB) while simultaneously maintaining a low rate of cellular proliferation. Immunolocalization of erbB receptors and heregulin-alpha suggests that heregulin-alpha localizes to the apical compartment and erbB receptors localize to the basolateral membrane. Epithelial injury results in activation of the receptors. This paradigm serves as a powerful system able to be activated the instant epithelial integrity is compromised. Thus, our overarching hypothesis is that alteration of airway epithelial integrity allows basolateral access of heregulin-alpha and other factors present in asthmatic airway surface liquid (ASL) and that this may play an important role in the pathogenesis of asthma. We propose to investigate three specific aims: 1. Do airway epithelia segregate ligand from receptor? 2. Is the airway epithelia barrier disrupted to allow ligand: receptor interaction by non-mechanical injuries? We will investigate two main hypotheses. 3. Is airway epithelial remodeling in asthma a consequence of altered ligand: receptor segregation? Our preliminary data suggests that disruption of the airway epithelial barrier results in a heregulin-alpha-mediated epithelial hyperplasia and hypertrophy, two hallmarks of airway remodeling in asthma. We hypothesize that in the asthmatic airways, alterations in the epithelial barrier play a central role in airway epithelial remodeling.

描述（由申请人提供）：哮喘是气道的异质疾病，其特征是慢性炎症，气道重塑，杯状细胞变质/增生，粘液分泌增加和支气管支气管高反应性。气道上皮主要是屏障，以防止吸入颗粒物，病毒和污染物进入肺部。上皮的极化性质使得紧密的连接处功能可以将根尖膜及其成分与基底外侧膜及其成分分开。我们的初步数据提供了这种障碍的重要性，该数据解释了人类气道上皮如何组成性地表达有丝分裂的配体（thee-gulin-alpha）及其受体（ERBB），而同时保持低细胞增殖速率。 ERBB受体和这里的藻蛋白-Alpha的免疫定位表明，这里调节蛋白-Alpha定位于顶端室，ERBB受体定位于基底外侧膜。上皮损伤导致受体的激活。该范式是一个强大的系统，能够激活即时上皮完整性受到损害。因此，我们的总体假设是，气道上皮完整性的改变允许哮喘气道表面液体（ASL）中存在的基底外侧访问和其他因素，并且这可能在哮喘的发病机理中起重要作用。我们建议研究三个具体目标：1。气道上皮是否会隔离受体的配体？ 2。气道上皮屏障是否被破坏以允许配体：非机械损伤的受体相互作用？我们将研究两个主要假设。 3。哮喘中的气道上皮重塑是配体改变的结果：受体分离吗？我们的初步数据表明，气道上皮屏障的破坏会导致这里进行glo蛋白 - α介导的上皮增生和肥大，这是哮喘中气道重塑的两个标志。我们假设在哮喘气道中，上皮屏障的改变在气道上皮重塑中起着核心作用。