Targeted Death of Collagen1a1-Expressing Fibroblasts Reduces Silica-Induced Pulmonary Fibrosis

表达胶原蛋白 1a1 的成纤维细胞的靶向死亡可减少二氧化硅诱导的肺纤维化

基本信息

批准号：
10751484
负责人：
Daniel G Foster
金额：
$ 3.31万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751484
关键词：
Ablation Address Affect Alveolus American Apoptosis Apoptotic Automobile Driving BCL2 gene Cells Cessation of life Cicatrix Collagen Dependence Deposition Development Diphtheria Disease Progression Dust Excision Exposure to Extracellular Matrix FDA approved Fibroblasts Fibrosis Flow Cytometry Gases Genetic Histologic Hydroxyproline Image Impairment Industry Inhalation Label Location Lung Measures Mediator Methods Mining Modeling Molecular Mus Myofibroblast Outcome Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Predisposition Process Proteins Pulmonary Fibrosis Pulse Oximetry Resistance Respiratory Failure Risk Risk Factors Signal Transduction Silicon Dioxide Silicosis Site Stains Structure of parenchyma of lung Testing Therapeutic Intervention Therapeutically Targetable Time Tissues Toxin Work diphtheria toxin receptor fibrotic lung fibrotic lung disease improved outcome in vivo evaluation inducible gene expression insight knock-down microCT mouse model novel novel therapeutic intervention prevent profibrotic fibroblast response wound healing

项目摘要

PROJECT SUMMARY A key feature of progressive fibrotic diseases of the lungs, including in patients with silicosis, is the excessive deposition of scar tissue and extracellular matrix (ECM), particularly collagen1a1 (Col1a1). Fibroblasts are known to be resistant to apoptosis and persist in fibrotic lungs, continuing to lay down matrix, contributing to a progressive and persistent phenotype in patients. Fibroblasts that participate in this pathogenic process have most commonly been identified by αSMA staining and termed myofibroblasts. However, recent work by our group and others has shown that αSMA does not identify all pathogenic fibroblasts in pulmonary fibrosis. This proposal seeks to address the central hypothesis that elimination of persistent collagen-producing fibroblasts is critical in halting disease progression. Based on our robust preliminary studies, we propose three specific aims to test this central hypothesis. Specific Aim 1 will determine the accumulation and localization of Col1a1+ fibroblasts to the fibrosis associated after silica exposure using a lineage tracing strategy. We hypothesize that Col1a1+ fibroblasts accumulate and persist in mouse lungs during silica-induced pulmonary fibrosis. In Aims 2 and 3 we ask if the loss of Col1a1+ fibroblasts prevents fibrosis progression. Specific Aim 2 will test the hypothesis that the progression of silica-induced pulmonary fibrosis in mice is arrested after the selective and targeted ablation of Col1a1+ fibroblasts. Specific Aim 3 will test the hypothesis that genetic loss of the anti-apoptotic protein Bcl-2 in Col1a1+ fibroblasts promotes their susceptibility to undergo intrinsic apoptosis during silica-induced pulmonary fibrosis resulting in the arrest of disease progression. There are currently no FDA approved therapies for silicosis and no therapies that stop or reverse fibrosis for pulmonary fibrosis in general. Thus, there is a critical need to identify molecular pathways or cell populations that are targetable for therapeutic intervention. Additionally, the proposed studies will provide a novel and mechanistic understanding about pathogenic fibroblast accumulation and persistence in driving the progression of silica-induced pulmonary fibrosis.

项目摘要肺进行性纤维化疾病的关键特征，包括硅化患者，是多余的疤痕组织和细胞外基质（ECM）的沉积，尤其是胶原蛋白1A1（COL1A1）。成纤维细胞是已知对凋亡具有抗性并持续存在于纤维化肺中，继续放置基质，有助于患者的进行性和持续表型。参与这种致病过程的成纤维细胞具有最常见的是αSMA染色并称为肌纤维细胞。但是，我们小组最近的工作其他人则表明，αSMA并未鉴定肺纤维化中的所有病原成纤维细胞。这个建议旨在解决持续产生胶原蛋白成纤维细胞的演变在中心假设中至关重要停止疾病进展。基于我们强大的初步研究，我们提出了三个特定目的来测试这一点中央假设。具体目标1将确定Col1a1+成纤维细胞的积累和定位二氧化硅暴露后使用谱系追踪策略相关的纤维化。我们假设Col1a1+成纤维细胞在二氧化硅诱导的肺纤维化过程中，在小鼠肺中积聚并持续存在。在目标2和3中，我们询问是否 COL1A1+成纤维细胞的丧失可防止纤维化进展。具体目标2将检验以下假设二氧化硅诱导的小鼠肺纤维化的进展在选择性后被捕并靶向消融 Col1a1+成纤维细胞。特定目标3将检验以下假设：抗凋亡蛋白Bcl-2在 COL1A1+成纤维细胞促进其在二氧化硅诱导的肺动物期间经历内在凋亡的敏感性纤维化导致疾病进展的停滞。目前没有FDA批准的硅疗法而且，没有疗法可以阻止或反向纤维化用于肺纤维化。那是迫切需要的确定适用于热干预目标的分子途径或细胞群。另外，拟议的研究将为致病性成纤维细胞积累提供新颖的机械理解以及驱动二氧化硅诱导的肺纤维化进展的持久性。