Role of lung endothelial cells during fibrotic lung remodeling

肺内皮细胞在纤维化肺重塑中的作用

基本信息

批准号：
10931822
负责人：
Tanya Kalin
金额：
$ 34.99万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10931822
关键词：
Attention Bleomycin Blood Vessels Blood capillaries Breast Cell Reprogramming Cell Survival Cells Chest Chronic Chronic Lung Injury Collagen DNA Data Deposition Development Disease Endothelial Cells Endothelium Epithelial Cells Epithelium FDA approved FOXF1 gene Family Fibroblasts Fibrosis Genes Genetic Genetic Transcription Goals Hepatocyte Human Hypoxia Immune Inflammation Inflammation Mediators Inflammatory Injury Interstitial Lung Diseases Kidney Lung Lung fibrogenesis Macrophage Mediator Modeling Molecular Mus Myofibroblast Nucleic Acid Regulatory Sequences Outcome Pathogenesis Pathologic Neovascularization Pathway interactions Patients Permeability Pharmaceutical Preparations Pirfenidone Play Process Pulmonary Fibrosis Pulmonary Inflammation Regulation Research Role Signal Pathway Signal Transduction System Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Vascular remodeling cell type efficacy testing endothelial dysfunction epithelial injury fibrogenesis fibrotic lung gene therapy idiopathic pulmonary fibrosis improved injured innovation irradiation lung injury lung microvascular endothelial cells lung repair mouse model nanoparticle nanoparticle delivery nintedanib novel novel therapeutic intervention novel therapeutics overexpression paracrine prevent programs promoter recruit repaired single-cell RNA sequencing transcription factor transcriptome sequencing vascular injury vector

项目摘要

Summary Chronic epithelial or vascular injuries followed by dysregulated repair are the trigger mechanisms in pathogenesis of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). Multiple cell types are involved in lung fibrogenesis, with fibroblasts and epithelial cells given the most attention. Role of endothelial cells and microvasculature remain unclear. Dysregulated repair causes vascular remodeling, associated with increased vessel permeability, partial loss of capillaries, focal increase in pathological angiogenesis and endothelial dysfunction. Normal endothelial cells (EC) are transcriptionally re-programmed into fibrosis- associated endothelial cells (FEC), that support activated fibroblasts and promote lung inflammation. Our long- term goal is to identify key regulators of EC-to-FEC re-programming and clarify molecular mechanisms of the crosstalk between endothelial cells and other cell types during pulmonary fibrogenesis. In our preliminary data, we used endothelial cells from lungs of patients with IPF and mouse lung fibrosis models to identify FOXF1 as a key transcriptional regulator of EC-to-FEC re-programming during lung fibrogenesis. Using transgenic mouse models with endothelial-specific deletion or over-expression of Foxf1 gene, we propose to test the hypothesis that endothelial FOXF1 decreases activation of fibroblasts and prevents macrophage accumulation in fibrotic foci. We propose two specific aims: (1) identify molecular mechanisms whereby endothelial FOXF1 inhibits lung fibrogenesis, (2) establish whether restoring FOXF1 in FECs will prevent or reduce fibrotic lung remodeling after chronic lung injury. Understanding the regulation of EC-to-TEC re-programming, and the molecular mechanisms utilized by pulmonary endothelial cells to control pulmonary fibrosis, will provide new approaches for treatment of interstitial lung diseases.

概括慢性上皮或血管损伤随后出现修复失调是触发机制间质性肺疾病的发病机制，包括特发性肺纤维化（IPF）。多种细胞类型是参与肺纤维化，其中成纤维细胞和上皮细胞最受关注。内皮细胞的作用细胞和微血管仍不清楚。修复失调会导致血管重塑，与血管通透性增加、毛细血管部分丧失、病理性血管生成局灶性增加和内皮功能障碍。正常内皮细胞（EC）被转录重编程为纤维化- 相关内皮细胞（FEC），支持激活的成纤维细胞并促进肺部炎症。我们的长期长期目标是确定 EC 到 FEC 重编程的关键调节因子，并阐明该过程的分子机制。肺纤维化过程中内皮细胞和其他细胞类型之间的串扰。在我们的初步数据中，我们使用来自 IPF 患者肺部的内皮细胞和小鼠肺纤维化模型将 FOXF1 鉴定为肺纤维化过程中 EC 至 FEC 重编程的关键转录调节因子。使用转基因小鼠内皮特异性删除或过度表达 Foxf1 基因的模型，我们建议检验该假设内皮细胞 FOXF1 减少成纤维细胞的活化并防止纤维化中巨噬细胞的积累焦点。我们提出两个具体目标：（1）确定内皮 FOXF1 抑制的分子机制肺纤维化，(2) 确定恢复 FEC 中的 FOXF1 是否会预防或减少肺纤维化慢性肺损伤后的重塑。了解 EC 到 TEC 重编程的规定，以及肺内皮细胞控制肺纤维化的分子机制将提供新的治疗间质性肺疾病的方法。