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的MUC5B的提高如何导致 蜂窝状囊肿形成，成纤维细胞积累，促纤维化编程和最终纤维化反应 远端气道和肺泡上皮损伤。通过在小鼠模型和中的体内研究结合 通过人类肺上皮细胞和成纤维细胞研究，项目3旨在通过测试来填补这一知识差距 远端气道上皮细胞中MUC5B Misexpression和持续的ER应力的假设会产生 肺泡上皮细胞和远端气道上皮细胞中凋亡的敏感性 纤维化和蜂窝状囊肿形成。我们将解决有关以下方面的机械问题：（i）如何 远端气道上皮细胞的muc5b misexpression创造了诱导凋亡的脆弱性 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囊肿的发育中 （iii）从补救的角度来看，如果预防上皮细胞凋亡会减轻肺的发展 纤维化和蜂窝状囊肿形成。虽然已经了解了肺泡上皮细胞的作用 纤维化发展中的凋亡，大多数研究是在发现增加之前进行的 MUC5B misexpression赋予的IPF敏感性。项目3旨在解决这一知识差距。目标1 将在远端气道MUC5B的背景下检验肺泡上皮细胞凋亡的假设 Misexpression，导致纤维化，但不能导致小鼠的蜂窝状囊肿形成。该假设将使用 在远端气道上皮细胞中MUC5B misexpress的背景下，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。 AIM 2将测试 假设在远端气道MUC5B的背景下诱导远端气道上皮细胞凋亡 Misexpression促进了小鼠的蜂窝状囊肿形成。使用远端气道测试该假设 上皮细胞消融策略。 AIM 2还将洞悉远端气道上皮的问题 在MUC5B missxpression中，细胞凋亡和蜂窝状囊肿形成间接导致肺泡 替代和纤维化。最后，AIM 3将检验预防肺泡和远端气道的假设 即使在远端气道MUC5B MISXPRESSION增加的背景下，上皮细胞凋亡也将阻止 持续的纤维化和蜂窝状囊肿形成。虽然远端气道中的MUC5B表达增加是一种风险 IPF患者中纤维化和蜂窝囊肿发展的因素，对基本知识知之甚少 连接这些事件的机制。虽然与项目1和2的广泛集成以及充分利用 在核心资源中，拟议研究的完成将创新对这些研究的研究 问题并提供有关MUC5B如何促进发展的尚未解决的问题的新颖见解 脆弱肺中的间质纤维化和蜂窝状囊肿。