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

项目摘要 进行性肺纤维化疾病的一个关键特征，包括在矽肺患者中，是过度的纤维化。 瘢痕组织和细胞外基质（ECM），特别是胶原1a1（Col1a1）的沉积。成纤维细胞是 已知抗细胞凋亡并在纤维化肺中持续存在，继续沉积基质，有助于 进行性和持续性表型。参与这一致病过程的成纤维细胞 最常通过αSMA染色鉴定，称为肌成纤维细胞。然而，我们小组最近的工作 其他研究表明，αSMA不能识别肺纤维化中的所有致病成纤维细胞。这项建议 试图解决中心假设，即消除持续的胶原蛋白产生的成纤维细胞是关键， 阻止疾病发展。基于我们强大的初步研究，我们提出了三个具体目标来测试这一点 中心假设特异性目的1将决定Col1a1+成纤维细胞在细胞中的积累和定位。 使用谱系追踪策略研究二氧化硅暴露后相关的纤维化。我们假设Col1a1+成纤维细胞 在二氧化硅诱导的肺纤维化期间在小鼠肺中积累并持续存在。在目标2和3中，我们问， Col1a1+成纤维细胞的损失防止纤维化进展。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和靶向消融 Col1a1+成纤维细胞。具体目标3将检验以下假设： COL1A1+成纤维细胞在二氧化硅诱导的肺损伤中促进其进行内在凋亡的易感性 纤维化导致疾病进展的停滞。目前没有FDA批准的矽肺治疗方法 并且一般来说没有停止或逆转肺纤维化的治疗方法。因此，迫切需要 鉴定可用于治疗干预的分子途径或细胞群。另夕h 拟议的研究将提供一个新的和机制的理解致病性成纤维细胞积累 并持续驱动二氧化硅诱导的肺纤维化的进展。

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.