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.

抽象的该计划的总体目标是了解MUC5B在建立脆弱肺和脆弱的肺部向肺的过渡，其特征是支气管肺泡上皮的持续损伤和肺成纤维细胞的激活。虽然我们的发现已经确定了一个新的分子（MUC5B）和目标（支气管肺泡上皮 HRCT扫描上的肺炎（UIP），表明需要再次受伤（第二次命中）来启动和加强纤维增生过程。根据我们的初步发现，我们假设在过表达的同时 MUC5B通过造成持续的支气管稳态ER应力来使个人有可能开发IPF的风险上皮，成纤维细胞募集和促纤维化编程需要第二次打击支气管上皮导致成纤维细胞的有害ER应力，募集和激活。我们的计划包括3个科学项目和4个核心，我们统一的科学主题包括：1）IPF是通过增强的表达来启动的 MUC5B（首次命中）建立了一个脆弱的肺部，其特征是持续的稳态ER压力大量UPR或凋亡）； 2）支气管肺泡上皮的继发损伤导致A过渡肺部易受伤害的肺，其特征是有害的ER应激（涉及大量UPR和凋亡）和以微支气管为中心的纤维增生的发展； 3）理解病因和初始远端气道上皮和AEC2细胞中的生物反应，以及支气管肺泡上皮的相互作用肺成纤维细胞将为预防疾病和早期干预创造机会。总体我们计划的假设是IPF的开发需要两次命中，MUC5B过表达支气管上皮影响，会影响体内稳态，启动反应和随后的伤害支气管上皮会导致有害的ER应激，异常上皮和成纤维细胞激活。项目1将一定地解决MUC5B过表达的驱动因素，项目2将确定确定词上皮损伤和有害的ER应力，项目3将研究分子界面 MUC5B诱导的上皮损伤和成纤维细胞激活。完成此高度集成计划时，我们将有：1）确定调节MUC5B诱导的损伤/修复过程的基本分子机制在纤维增殖中； 2）定义的机制，该机制将创建用于主要和次要干预的路线图 IPF; 3）为早期干预疾病提供了理由和目标，这仍然是重要的公众健康问题，可能会增加兴奋后。