权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms Regulating Lung Injury and Early Lung Fibrosis

肺损伤和早期肺纤维化的调节机制

基本信息

批准号：
10627593
负责人：
David Albert Schwartz
金额：
$ 245.07万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627593
关键词：
Address Aging Apoptosis Apoptosis Promoter Biological Bleomycin Bronchioles Cells Cyst Development Disease Disease model Distal Dominant Genetic Conditions Early Intervention Enhancers Epigenetic Process Epithelial Cells Epithelium Etiology Event Exposure to Fibroblasts Fibrosis Functional disorder Goals Heat shock proteins In Vitro Individual Inflammation Injury Intervention Lung MUC5B gene Microscopic Modeling Molecular Mus Pathogenesis Pathogenicity Pathologic Patients Phenotype Physiological Predisposition Process Public Health Pulmonary Fibrosis Reporting Research Risk Risk Factors Role Scanning Stress Structure of parenchyma of lung Tobacco smoke Usual Interstitial Pneumonia Variant airway epithelium alveolar epithelium biological adaptation to stress disorder prevention drug development endoplasmic reticulum stress epigenetic regulation epithelial injury gain of function genetic variant idiopathic pulmonary fibrosis injury and repair lung injury new therapeutic target non-genetic novel overexpression post-COVID-19 prevent preventive intervention programs promoter recruit respiratory response

项目摘要

ABSTRACT The overall goal of this Program is to understand the role of MUC5B in establishing a vulnerable lung and the transition of a vulnerable lung to a lung characterized by persistent injury of bronchoalveolar epithelia and activation of lung fibroblasts. While our findings have identified a novel molecule (MUC5B) and target (bronchoalveolar epithelia) for IPF, only ≈5% of individuals with this genetic variant develop usual interstitial pneumonia (UIP) on HRCT scan, suggesting the need for another insult (a ‘second hit’) to initiate and intensify the fibroproliferative process. Based on our preliminary findings, we postulate that while overexpression of MUC5B places individuals at risk of developing IPF by causing persistent homeostatic ER stress of bronchiolar epithelia, fibroblast recruitment and pro-fibrotic programming requires a second hit to the bronchiolar epithelia resulting in detrimental ER stress and recruitment and activation of fibroblasts. Our Program includes 3 Scientific Projects and 4 Cores, and our unifying scientific themes include: 1) IPF is initiated by enhanced expression of MUC5B (first hit) that establish a vulnerable lung characterized by persistent homeostatic ER stress (without substantial UPR or apoptosis); 2) secondary injury to the bronchoalveolar epithelia results in transition of a vulnerable lung to a lung characterized by detrimental ER stress (involving substantial UPR and apoptosis) and the development of microscopic bronchiolar-centric fibroproliferation; and 3) understanding etiologic and initial biological responses in distal airway epithelia and AEC2 cells, and the interaction of bronchoalveolar epithelia with lung fibroblasts will create opportunities for disease prevention and early intervention. The overarching hypothesis of our Program is that the development of IPF requires two hits, MUC5B overexpression in bronchiolar epithelia that induces a homeostatic, priming response and subsequent injury of the bronchiolar epithelia that results in detrimental ER stress, aberrant epithelia, and fibroblast activation. Project 1 will definitively address the drivers of MUC5B overexpression, Project 2 will identify the determinants of epithelial injury and detrimental ER stress, and Project 3 will investigate the molecular interface between MUC5B-induced epithelial injury and fibroblast activation. At the completion of this highly integrated Program, we will have: 1) established the basic molecular mechanisms that regulate MUC5B-induced injury/repair process in fibroproliferation; 2) defined mechanisms that will create a roadmap for primary and secondary intervention in IPF; and 3) provided a rationale and targets for early intervention in a disease that remains a significant public health problem and may increase post-Covid.

摘要