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Role of p73 in COPD Pathogenesis

p73 在 COPD 发病机制中的作用

基本信息

批准号：
10084226
负责人：
Bradley Winston Richmond
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084226
关键词：
Apical Award Carrier Proteins Cause of Death Cell Differentiation process Cells Chronic Chronic Obstructive Airway Disease Communities Complex Data Defect Development Epithelial Epithelial Cells Fibrosis Functional disorder Genetic Transcription Goblet Cells Human Hyperplasia IgA Deficiency Immune Immunofluorescence Microscopy Immunoglobulin A Impairment In Vitro Individual Inflammation Inflammatory Lesion Link Lung Lung diseases Measures Mediating Molecular Chaperones Mucosal Immunity Mucous Membrane Mus Pathogenesis Patients Phenotype Play Polymeric Immunoglobulin Receptors Publishing Pulmonary Emphysema Role Secretory Immunoglobulin A Smoker Squamous Metaplasia Stimulus Structure Surface Techniques Testing Tracheal Epithelium Training Transgenic Mice United States Veterans airway epithelium airway inflammation airway obstruction airway remodeling base bronchial epithelium cigarette smoke environmental tobacco smoke exposure epithelial injury exposure to cigarette smoke former smoker in vivo lung injury microbial morphogens mouse model non-smoking overexpression prevent receptor expression smoking cessation smoking-related lung disease tobacco smoke exposure transcription factor transcytosis

项目摘要

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and has no cure. While the association between chronic tobacco smoke exposure and COPD has been known for decades, the reasons for ongoing lung damage in COPD after smoking cessation remain undefined. We and others have shown that epithelial remodeling with loss of multiciliated cells (MCCs) is widespread in the airways of COPD patients and abnormal epithelial differentiation in individual small airways is strongly associated with loss of the secretory IgA (SIgA) barrier, chronic inflammation, and fibrotic remodeling of the airway wall. Further, we showed that loss of SIgA in the airways is sufficient to induce a COPD-like phenotype in mice, suggesting altered mucosal immunity plays a causal role in COPD pathogenesis. In this proposal, we will focus on the underlying cause of impaired mucosal immunobarrier function which we believe to abnormal epithelial differentiation. Our preliminary data demonstrate that the differentiation factor p73, recently shown to be required for the MCC development, is required for MCC-specific expression of a transport protein required for SIgA transcytosis (polymeric immunoglobulin receptor or pIgR). We found that cigarette smoke suppresses p73 expression in vitro and in vivo, providing a mechanistic link between cigarette smoke exposure, abnormal epithelial differentiation, and impaired mucosal immunobarrier function. In this proposal, we will test the hypothesis that cigarette smoke suppresses p73, resulting in loss of MCCs, reduced pIgR expression and SIgA transcytosis, and impaired immunobarrier function. In Aim 1, we will investigate the impact of targeted deletion of p73 or pIgR in FoxJ1-expressing multiciliated cells on airway epithelial differentiation and immune defense. In Aim 2 we will identify p73-dependent transcription factors that regulate pIgR in murine tracheal epithelial cells and validate our findings in primary human bronchial epithelial cells. In Aim 3 we will define the relationships between cigarette smoke, p73 expression, and epithelial differentiation in vivo. Together, these studies will determine how defects in normal epithelial differentiation result in alterations in mucosal immunity and evaluate whether p73 represents a mechanistic link between chronic inflammation and MCC loss.

项目总结