Reducing Fibroblast Persistence in Pulmonary Fibrosis as a Mechanism of Resolution

减少肺纤维化中成纤维细胞的持久性作为解决机制

• 批准号: 10661572
• 负责人: Elizabeth Frances Redente
• 金额: $ 54.76万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661572
• 关键词: Ablation; Acceleration; Address; Affect; Alveolar; Alveolar fibrosis; Apoptosis; Apoptotic; Asia; BCL2 gene; Blood capillaries; Cessation of life; Coal; Collagen; Deposition; Development; Diagnosis; Disease; Dust; Environment; Equation; Exposure to; Extracellular Matrix; Female; Fibroblasts; Fibrosis; Flow Cytometry; Gases; Human; Impairment; Inhalation; Interstitial Lung Diseases; Link; Lung; Lung diseases; Mediating; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Occupational; Organ; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Play; Poison; Population; Process; Prognosis; Proteins; Pulmonary Fibrosis; Resistance; Resolution; Respiratory Failure; Risk; Risk Factors; Role; Signal Transduction; Silicates; Silicon Dioxide; Testing; Therapeutic; Therapeutic Intervention; Therapeutically Targetable; Tissues; United States; Veterans; Work; X-Ray Computed Tomography; alveolar epithelium; cigarette smoke; cigarette smoking; clinically relevant; effective therapy; epithelial injury; fibrotic lung; fibrotic lung disease; genetic approach; improved outcome; in vivo; inhibitor; insight; male; microCT; mortality; novel; novel therapeutic intervention; particle; prevent; profibrotic fibroblast; response; small molecule inhibitor; therapeutic target

Project Summary Interstitial lung diseases (ILD) include a devastating group of fibrotic parenchymal diseases with high morbidity and mortality, for which there are limited effective therapies. Pulmonary fibrosis (PF) develops in ILD patients in response to alveolar epithelial injury and the subsequent activation and accumulation of pro-fibrotic fibroblasts, which deposit collagen and other extracellular matrix (ECM) components. The accumulation and persistence of pro-fibrotic fibroblasts and the deposition of ECM leads to progressive fibrosis resulting in declining gas exchange in the alveolar-capillary units. The inhalation of silicate dust, cigarette smoke and toxic chemicals are known risk factors for developing fibrotic lung disease and these exposures have disproportionally affected US veteran's, coal miners and construction workers. PF is generally believed to be irreversible. Consequently, it becomes increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the central hypothesis that the development of pro-fibrotic fibroblast resistance to apoptosis contributes to progressive fibrotic disease. Furthermore, we propose that expression of the anti-apoptotic gene Bcl-2 plays a central role in mediating the persistence of pro-fibrotic fibroblasts. Based on robust preliminary studies in a silica-induced model of pulmonary fibrosis, we propose testing this central hypothesis with 3 specific aims: Specific Aim 1 will test the hypothesis that in vivo ablation of pro-fibrotic lung fibroblasts will induce the resolution of persistent pulmonary fibrosis initiated by the intratracheal instillation of silica particles. Specific Aim 2 will test the hypothesis that reducing the resistance to apoptosis in pro-fibrotic fibroblasts promotes the resolution of progressive pulmonary fibrosis. This hypothesis will be tested using a genetic approach to determine if conditional deletion of the anti-apoptotic gene Bcl-2 in pro-fibrotic fibroblasts leads to the apoptosis of fibrotic lung fibroblasts and the resolution of persistent fibrosis in a model of silica-induced pulmonary fibrosis. Specific Aim 3 will test the hypothesis that clinically relevant Bcl-2 inhibitors will therapeutically target pro- fibrotic fibroblasts and promote the resolution of established pulmonary fibrosis. This hypothesis will be tested by treating mice with a small molecule inhibitor to reduce Bcl-2 activity, prevent fibroblast survival and promote the resolution of persistent fibrosis in vivo. Mice will be followed using micro-CT imaging to monitor disease development, progression and resolution. The proposed studies will provide new understanding about the targeting of pro-fibrotic fibroblasts for death and how this may aid in the resolution of fibrosis. Furthermore, the outcome of this work should significantly impact our understanding of the mechanisms that control the resolution of fibrosis and its persistence in other organs and tissues.

项目概要 间质性肺疾病 (ILD) 包括一组破坏性的纤维化实质疾病，其发病率很高。 发病率和死亡率，对此有效的治疗方法有限。 ILD 中出现肺纤维化 (PF) 患者对肺泡上皮损伤以及随后促纤维化的激活和积累的反应 成纤维细胞，沉积胶原蛋白和其他细胞外基质 (ECM) 成分。积累与 促纤维化成纤维细胞的持续存在和 ECM 的沉积导致进行性纤维化，从而导致 肺泡毛细血管单位的气体交换下降。吸入硅酸盐粉尘、香烟烟雾和有毒物质 化学物质是导致纤维化肺病的已知危险因素，这些接触已 美国退伍军人、煤矿工人和建筑工人受到的影响尤为严重。一般认为PF 不可逆转的。因此，识别可靶向的分子途径变得越来越重要 进行治疗干预。该提案旨在通过调查中央机构来解决这一未满足的需求 假设促纤维化成纤维细胞对细胞凋亡的抵抗力的发展有助于进行性 纤维化疾病。此外，我们认为抗凋亡基因 Bcl-2 的表达起着核心作用 介导促纤维化成纤维细胞的持续存在。基于二氧化硅诱导的强有力的初步研究 肺纤维化模型，我们建议通过 3 个具体目标来检验这一中心假设： 具体目标 1 将检验以下假设：促纤维化肺成纤维细胞的体内消融将诱导持久性问题的解决 由气管内滴注二氧化硅颗粒引发的肺纤维化。具体目标 2 将测试 假设降低促纤维化成纤维细胞对细胞凋亡的抵抗力可促进纤维化的解决 进行性肺纤维化。该假设将使用遗传方法进行测试，以确定是否 促纤维化成纤维细胞中抗凋亡基因Bcl-2的条件性缺失导致纤维化细胞凋亡 肺成纤维细胞和二氧化硅诱导的肺纤维化模型中持续性纤维化的解决。 具体目标 3 将检验以下假设：临床相关的 Bcl-2 抑制剂将治疗靶向亲 纤维化成纤维细胞并促进已形成的肺纤维化的消退。这个假设将被检验 通过用小分子抑制剂治疗小鼠来降低 Bcl-2 活性，防止成纤维细胞存活并促进 体内持续性纤维化的消退。将使用微型 CT 成像跟踪小鼠以监测疾病 发展、进展和解决。拟议的研究将为人们提供新的认识 针对促纤维化成纤维细胞的死亡以及这如何有助于解决纤维化。此外， 这项工作的成果应该会极大地影响我们对控制机制的理解 纤维化的消退及其在其他器官和组织中的持续存在。