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：
10646265
负责人：
Tanya Kalin
金额：
$ 18.83万
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 2023-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646265
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修复失调是触发机制间质性肺部疾病的发病机理，包括特发性肺纤维化（IPF）。多种单元格是参与肺纤维发生，具有成纤维细胞和上皮细胞的关注。内皮的作用细胞和微脉管系统尚不清楚。失调的维修失调会导致血管重塑，与增加血管通透性，毛细血管的部分损失，病理血管生成的局灶性增加和内皮功能障碍。正常内皮细胞（EC）在转录上重新编程为纤维化 - 相关的内皮细胞（FEC），支持活化的成纤维细胞并促进肺部炎症。我们的长期术语目标是确定EC至FEC重新编程的关键调节因子并阐明分子机制肺纤维发生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了来自IPF和小鼠肺纤维化模型患者肺的内皮细胞来识别FOXF1 肺纤维发生过程中EC至FEC重新编程的关键转录调节剂。使用转基因鼠标我们提议检验假设这种内皮FOXF1降低了成纤维细胞的激活并防止巨噬细胞积累焦点。我们提出了两个具体目的：（1）确定内皮FOXF1抑制分子机制肺纤维发生，（2）确定在FEC中恢复FOXF1是否会预防或减少纤维化肺慢性肺损伤后进行改造。了解EC至TEC重新编程的调节，以及肺内皮细胞利用的分子机制来控制肺纤维化，将提供新的治疗间质肺疾病的方法。