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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：
10275717
负责人：
Tanya Kalin
金额：
$ 55.08万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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/10275717
关键词：
Attention Bleomycin Blood Vessels Blood capillaries Breast Cell Survival Cells Chest Chronic Collagen DNA Data Deposition Development Disease Endothelial Cells Endothelium Epithelial Epithelial Cells FDA approved FOXF1 gene Family Fibroblasts Fibrosis Genes Genetic Genetic Transcription Goals Hepatocyte Human Hypoxia Immune Inflammation Inflammatory Injury Interstitial Lung Diseases Kidney Lung Lung Inflammation Mediator of activation protein Modeling Molecular Mus Myofibroblast Nucleic Acid Regulatory Sequences Outcome Pathogenesis Pathologic Neovascularization Pathway interactions Patients Permeability Pharmaceutical Preparations Pirfenidone Play Process Pulmonary Fibrosis Regulation Research Role Signal Pathway Signal Transduction Sum System Testing Therapeutic Tissues Transgenic Mice Transgenic Organisms Vascular remodeling base cell type efficacy testing endothelial dysfunction epithelial injury fibrogenesis gene therapy idiopathic pulmonary fibrosis improved injured innovation irradiation lung injury lung repair macrophage mouse model nanoparticle nanoparticle delivery novel novel strategies 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.

摘要慢性上皮损伤或血管损伤伴随着失调的修复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)。多种单元格类型包括参与肺纤维化的发生，以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系统仍不清楚。失调的修复导致血管重塑，与血管通透性增加，部分毛细血管丧失，病理性血管生成局灶性增加内皮功能障碍。正常的内皮细胞(EC)被转录重新编程为纤维化- 相关内皮细胞(FEC)，支持活化的成纤维细胞并促进肺部炎症。我们的长- 学期目标是确定EC-to-FEC重新编程的关键调控因子，并阐明肺纤维化形成过程中内皮细胞与其他细胞类型之间的串扰。在我们的初步数据中，我们使用IPF患者的肺内皮细胞和小鼠肺纤维化模型来鉴定FOXF1是肺纤维化过程中EC-to-FEC重新编程的关键转录调节因子。使用转基因小鼠 Foxf1基因内皮细胞特异性缺失或过度表达的模型，我们建议检验这一假设血管内皮细胞FOXF1降低成纤维细胞活化和防止巨噬细胞在纤维化中聚集焦点。我们提出两个具体目标：(1)确定内皮FOXF1抑制FOXF1的分子机制肺纤维化，(2)确定在FECs中恢复FOXF1是否可以预防或减少纤维化的肺慢性肺损伤后的重塑。了解EC到TEC重新编程的规则，以及肺内皮细胞控制肺纤维化的分子机制，将提供新的间质性肺疾病的治疗方法。