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.

项目概要进行性肺部纤维化疾病（包括矽肺患者）的一个关键特征是过度吸入疤痕组织和细胞外基质 (ECM)，特别是胶原蛋白 1a1 (Col1a1) 的沉积。已知对细胞凋亡有抵抗力，并持续存在于纤维化的肺中，继续铺设基质，有助于参与这一致病过程的成纤维细胞具有进行性和持续性的表型。最常见的是通过 αSMA 染色来识别并称为肌成纤维细胞，然而，我们小组最近的工作。等人表明，αSMA 并不能识别肺纤维化中的所有致病性成纤维细胞。试图解决一个中心假设，即消除持续产生胶原蛋白的成纤维细胞对于根据我们强有力的初步研究，我们提出了三个具体目标来测试这一点。中心假设。具体目标 1 将确定 Col1a1+ 成纤维细胞的积累和定位。我们使用谱系追踪策略观察了二氧化硅暴露后相关的纤维化。在二氧化硅诱导的肺纤维化过程中，它们在小鼠肺部积聚并持续存在。在目标 2 和 3 中，我们询问是否 Col1a1+ 成纤维细胞的缺失可防止纤维化进展。具体目标 2 将检验以下假设：在选择性和有针对性的消融硅后，二氧化硅诱导的小鼠肺纤维化的进展被阻止 Col1a1+ 成纤维细胞将检验抗凋亡蛋白 Bcl-2 基因缺失的假设。 Col1a1+ 成纤维细胞在二氧化硅诱导的肺损伤过程中促进其发生内在凋亡的易感性纤维化导致疾病进展停滞目前尚无 FDA 批准的矽肺治疗方法。一般来说，没有治疗方法可以阻止或逆转肺纤维化，因此，迫切需要这样做。识别可用于治疗干预的分子途径或细胞群。拟议的研究将为致病性成纤维细胞积累提供新颖和机制的理解以及持续驱动二氧化硅诱导的肺纤维化的进展。