Mechanisms Regulating Lung Injury and Early Lung Fibrosis

肺损伤和早期肺纤维化的调节机制

• 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
• 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

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 该项目的总体目标是了解MUC 5 B在建立脆弱肺中的作用， 脆弱肺转变为以支气管肺泡上皮细胞持续损伤为特征的肺， 肺成纤维细胞的活化。虽然我们的研究结果已经确定了一种新的分子（MUC 5 B）和靶点， 对于IPF（支气管肺泡上皮细胞），只有0.5%的具有这种遗传变异的个体发生通常的间质性 HRCT扫描显示肺炎（UIP），提示需要另一次损伤（“第二次打击”）来启动和加强 纤维增生过程基于我们的初步发现，我们假设，虽然过度表达 MUC 5 B通过引起细支气管上皮细胞的持续稳态ER应激，使个体处于发展IPF的风险中。 上皮细胞、成纤维细胞募集和促纤维化编程需要对细支气管上皮细胞进行第二次打击 导致有害的ER应激以及成纤维细胞的募集和活化。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是由增强表达 MUC 5 B（第一次击中）建立以持续稳态ER应激为特征的脆弱肺（没有 大量的UPR或凋亡）; 2）对支气管肺泡上皮细胞的继发性损伤导致 肺对以有害的ER应激（涉及大量UPR和细胞凋亡）为特征的肺脆弱， 显微镜下细支气管中心性纤维增生的发展; 3）了解病因和初始 远端气道上皮细胞和AEC 2细胞的生物学反应，以及支气管肺泡上皮细胞的相互作用 将为疾病预防和早期干预创造机会。总体 我们项目的假设是，IPF的发生需要两次打击， 细支气管上皮细胞，诱导稳态，引发反应和随后的损伤， 细支气管上皮细胞，导致有害的ER应激、异常上皮细胞和成纤维细胞活化。 项目1将明确解决MUC 5 B过表达的驱动因素，项目2将确定MUC 5 B过表达的决定因素。 上皮损伤和有害的ER应激，项目3将研究分子界面之间 MUC 5 B诱导的上皮损伤和成纤维细胞活化。在完成这一高度一体化的方案后， 我们将：1）建立MUC 5 B诱导损伤/修复过程的基本分子调控机制 在纤维增生; 2）定义的机制，将创建一个路线图的主要和次要干预， IPF;以及3）提供了早期干预仍然是重大公众问题的疾病的理由和目标 健康问题，并可能在新冠肺炎后增加。