Targeting early events in MUC5B-driven lung injury and fibrosis

针对 MUC5B 驱动的肺损伤和纤维化的早期事件

• 批准号: 10627600
• 负责人: David W. Riches
• 金额: $ 54.12万
• 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/10627600
• 关键词: Ablation; Address; Alleles; Alveolar; Apoptosis; Apoptotic; Cells; Chronic; Cyst; Development; Distal; Epithelial Cells; Epithelium; Event; Extrinsic allergic alveolitis; Fibroblasts; Fibrosis; Goals; Human; In Vitro; Individual; Induction of Apoptosis; Injury; Interstitial Lung Diseases; Knowledge; Learning; Lung; MUC5B gene; Maps; Medial; Methods; Minor; Modeling; Mus; Pathogenesis; Pathologic; Patients; Predisposition; Prevention; Proteins; Pulmonary Fibrosis; Repression; Resources; Rheumatoid Arthritis; Risk Factors; Role; System; Testing; Tissues; Variant; airway epithelium; alveolar epithelium; endoplasmic reticulum stress; epithelial injury; gain of function; genetic variant; idiopathic pulmonary fibrosis; in vivo; innovation; insight; interstitial; lung injury; mouse model; novel; prevent; profibrotic fibroblast; promoter; response

PROJECT SUMMARY The overall goal of Project 3 is to understand how increased misexpression of MUC5B in distal airways leads to honeycomb cyst formation, fibroblast accumulation, pro-fibrotic programming and ultimately fibrosis in response to distal airway and alveolar epithelial injury. Through a combination of in vivo studies in mouse models and in vitro studies with human lung epithelial cells and fibroblasts, Project 3 seeks to fill this knowledge gap by testing the hypothesis that MUC5B misexpression and persistent ER stress in distal airway epithelial cells creates susceptibility to apoptosis in both alveolar epithelial cells and distal airway epithelial cells leading to fibrosis and honeycomb cyst formation, respectively. We will address mechanistic questions about: (i) how MUC5B misexpression by distal airway epithelial cells creates vulnerability to apoptosis induction leading to fibroblast accumulation, pro-fibrotic programming, fibrosis and honeycomb cyst formation, (ii) the relative role(s) of alveolar and distal airway epithelial cell apoptosis in the development of fibrosis and honeycomb cysts, and (iii) from a remedial perspective, if prevention of epithelial cell apoptosis mitigates the development of pulmonary fibrosis and honeycomb cyst formation. While much has been learned about the role of alveolar epithelial cell apoptosis in the development of fibrosis, most of these studies were conducted prior to the discovery of increased IPF susceptibility conferred by MUC5B misexpression. Project 3 seeks to address this knowledge gap. Aim 1 will test the hypothesis that alveolar epithelial cell apoptosis, in the context of increased distal airway Muc5b misexpression, leads to fibrosis, but not honeycomb cyst formation in mice. This hypothesis will be tested using an alveolar epithelial cell ablation strategy in the context of Muc5b misexpression in distal airway epithelial cells to define the importance of alveolar epithelial cell apoptosis in the development of fibrosis. Aim 2 will test the hypothesis that induction of distal airway epithelial cell apoptosis in the context of increased distal airway Muc5b misexpression promotes honeycomb cyst formation in mice. This hypothesis with be tested using a distal airway epithelial cell ablation strategy. Aim 2 will also provide insight into the question of whether distal airway epithelial cell apoptosis and honeycomb cyst formation in the context of Muc5b misexpression indirectly leads to alveolar replacement and fibrosis. Lastly, Aim 3 will test the hypothesis that prevention of alveolar and distal airway epithelial cell apoptosis even in the context of increased distal airway Muc5b misexpression will prevent persistent fibrosis and honeycomb cyst formation. While increased MUC5B expression in distal airways is a risk factor for the development of fibrosis and honeycomb cysts in IPF patients, little is known about the fundamental mechanisms that connect these events. Though extensive integration with Projects 1 and 2 and full utilization of the Core resources, completion of the proposed studies will innovate understanding of these understudied questions and provide novel insights into the unresolved question of how MUC5B contributes to the development of interstitial fibrosis and honeycomb cysts in the vulnerable lung.

项目概要 项目 3 的总体目标是了解远端气道中 MUC5B 错误表达的增加如何导致 蜂窝状囊肿形成、成纤维细胞积聚、促纤维化编程以及最终纤维化反应 致远端气道和肺泡上皮损伤。通过小鼠模型和体内研究的结合 人类肺上皮细胞和成纤维细胞的体外研究，项目 3 试图通过测试来填补这一知识空白 远端气道上皮细胞中 MUC5B 错误表达和持续 ER 应激造成的假设 肺泡上皮细胞和远端气道上皮细胞均易发生凋亡，导致 分别是纤维化和蜂窝状囊肿形成。我们将解决以下机械问题：（i）如何 远端气道上皮细胞的 MUC5B 错误表达会导致细胞凋亡诱导的脆弱性，从而导致 成纤维细胞积累、促纤维化编程、纤维化和蜂窝状囊肿形成，(ii) 相对作用 肺泡和远端气道上皮细胞凋亡在纤维化和蜂窝状囊肿发展中的作用，以及 (iii) 从治疗的角度来看，如果预防上皮细胞凋亡可以减轻肺病的发展 纤维化和蜂窝状囊肿形成。虽然人们对肺泡上皮细胞的作用已经了解很多 细胞凋亡在纤维化发展中的作用，大多数这些研究是在发现细胞凋亡增加之前进行的 MUC5B 错误表达导致 IPF 易感性。项目 3 旨在解决这一知识差距。目标1 将检验在远端气道 Muc5b 增加的情况下肺泡上皮细胞凋亡的假设 错误表达会导致小鼠纤维化，但不会导致蜂窝状囊肿形成。该假设将使用以下方法进行检验 远端气道上皮细胞 Muc5b 错误表达背景下的肺泡上皮细胞消融策略 定义肺泡上皮细胞凋亡在纤维化发展中的重要性。目标 2 将测试 假设在远端气道 Muc5b 增加的情况下诱导远端气道上皮细胞凋亡 错误表达促进小鼠蜂窝状囊肿形成。该假设可以使用远端气道进行测试 上皮细胞消融策略。目标 2 还将深入探讨远端气道上皮细胞是否 Muc5b 错误表达背景下的细胞凋亡和蜂窝状囊肿形成间接导致肺泡 置换和纤维化。最后，目标 3 将检验以下假设：预防肺泡和远端气道 即使在远端气道 Muc5b 错误表达增加的情况下，上皮细胞凋亡也会阻止 持续纤维化和蜂窝状囊肿形成。虽然远端气道中 MUC5B 表达增加是一种风险 IPF 患者发生纤维化和蜂窝状囊肿的因素，但对其基本原理知之甚少 连接这些事件的机制。通过与项目1、2的广泛整合并充分利用 的核心资源，完成拟议的研究将加深对这些研究对象的理解 问题并对 MUC5B 如何促进发展这一未解决的问题提供新颖的见解 脆弱肺部的间质纤维化和蜂窝状囊肿。