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.

项目摘要 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、促纤维化程序化和最终纤维化反应 远端气道和肺泡上皮损伤。通过结合小鼠模型中的体内研究和 项目3通过对人肺上皮细胞和成纤维细胞的体外研究， 远端气道上皮细胞中MUC5B的错误表达和持续的ER应激 肺泡上皮细胞和远端气道上皮细胞对凋亡的敏感性， 纤维化和蜂窝囊肿形成。我们将解决机械问题：（一）如何 远端气道上皮细胞的MUC5B错误表达导致易受凋亡诱导， 成纤维细胞积聚、促纤维化编程、纤维化和蜂窝囊肿形成，（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囊肿的发展， (iii)从治疗的角度来看，如果预防上皮细胞凋亡减轻了肺动脉高压的发展， 纤维化和蜂窝囊肿形成。虽然人们对肺泡上皮细胞的作用已经有了很多了解， 细胞凋亡在纤维化发展中的作用，这些研究中的大多数都是在发现细胞凋亡增加之前进行的。 MUC5B错误表达引起的IPF易感性项目3旨在弥补这一知识差距。要求1 将检验肺泡上皮细胞凋亡的假设，在远端气道Muc5b增加的情况下， 错表达导致纤维化，但不会在小鼠中形成蜂窝状囊肿。该假设将通过以下方式进行检验： 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 明确肺泡上皮细胞凋亡在纤维化发生发展中的重要性。目标2将测试 在远端气道Muc5b增加背景下诱导远端气道上皮细胞凋亡的假设 错表达促进小鼠蜂窝状囊肿形成。使用远端气道测试该假设 上皮细胞消融策略。目的2还将提供对远端气道上皮是否 在Muc5b错误表达的背景下，细胞凋亡和蜂窝囊肿形成间接导致肺泡 替换和纤维化。最后，目标3将检验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 持续性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患者纤维化和蜂窝状囊肿发生的因素，关于其基本机制知之甚少。 连接这些事件的机制。虽然与项目1和2广泛整合， 核心资源，完成拟议的研究将创新对这些未充分研究的理解 问题，并为MUC5B如何促进发展的未解决问题提供新的见解 间质纤维化和蜂窝状囊肿。