权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
9795882
负责人：
Elizabeth Frances Redente
金额：
$ 52.42万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
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/9795882
关键词：
Ablation Address Affect Alveolar Apoptosis Apoptotic Asia BCL2 gene Blood capillaries Cessation of life Cicatrix Coal Collagen Deposition Development Diagnosis Disease Dust Epithelial Exposure to Extracellular Matrix Female Fibroblasts Fibrosis Flow Cytometry Gases Human Impairment Inhalation Injury Interstitial Lung Diseases Investigational Therapies Link Lung Lung diseases Mediating Methods Modeling Molecular Monitor Morbidity - disease rate Mus Occupational Organ Outcome Pathway interactions Patient-Focused Outcomes Patients Play Poison Population Process Proteins Pulmonary Fibrosis Resistance Resolution Respiratory Failure Risk Risk Factors Role Signal Transduction Silicates Silicon Dioxide Testing Therapeutic Therapeutic Intervention Tissues United States Veterans Work X-Ray Computed Tomography base cigarette smoke cigarette smoking clinically relevant effective therapy genetic approach improved outcome in vivo inhibitor/antagonist insight knock-down male microCT mortality novel novel therapeutics outcome forecast particle prevent response small molecule inhibitor targeted treatment therapeutic target

项目摘要

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.

项目总结