Functional diversity of lung pericytes in lung injury

肺损伤中肺周细胞的功能多样性

基本信息

批准号：
10561461
负责人：
Chi F Hung
金额：
$ 63.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561461
关键词：
ANGPTL4 gene Acute Acute Lung Injury Acute Respiratory Distress Syndrome Affect Alveolar Angiogenic Factor Angiopoietins Attenuated Biology Blood Platelets Blood Vessels CC chemokine receptor 2 CCL2 gene CCL7 gene Cell Adhesion Molecules Cell Nucleus Cells Data Detection Development Emigrations Endothelial Cells Endothelium Epithelial Cells Epithelium Functional disorder Future Genes Genetic Transcription Goals Individual Inflammation Inflammatory Inflammatory Response Influenza Injury Intercellular adhesion molecule 1 Kidney Lead Leukocytes Ligands Lung Lung infections Maintenance Mediating Modeling Molecular Molecular Profiling Morbidity - disease rate Muscle Organ Pathogenesis Pathogenicity Pattern Pericytes Permeability Phenotype Play Population Positioning Attribute Publishing Regulation Research Resolution Risk Risk Factors Role Sentinel Signal Pathway Signal Transduction Skin Stromal Cells Surface Testing Therapeutic Intervention Tissues United States Up-Regulation Vascular Diseases Viral Pneumonia Viral Respiratory Tract Infection Work alveolar epithelium angiogenesis cell type chemokine clinically relevant combinatorial cytokine immunoregulation improved indexing influenza infection influenza pneumonia insight interstitial interstitial cell intravital microscopy lung development lung injury lung repair migration monocyte mortality mouse model neutrophil novel novel therapeutic intervention programs recruit response response to injury segregation targeted treatment tissue injury tissue repair trafficking transcriptome sequencing transcriptomics vasculogenesis

项目摘要

ABSTRACT Pericytes have been implicated in lung injury and repair in a number of organs. Our research focuses on the role of lung stromal subpopulations in tissue injury and repair, and our recent work revealed lung pericytes may have multiple functional roles during injury. Data from transcriptomic analyses of activated lung pericytes reveal upregulation of multiple genes involved in inflammation, angiogenesis, and matrix remodeling. The goal of this project is to characterize the functional diversity of pericytes in their response to a clinically relevant model of lung injury – influenza infection. To achieve this goal, we will test hypotheses on the roles of pericytes in endothelial and immune regulation. In Aim 1, we will investigate the mechanisms of pericyte-endothelial cell crosstalk that lead to activation of endothelial cells and increased lung permeability. Angiopoietin-L4 (ANGPTL4) has been implicated as a hyperpermeability factor that is also highly upregulated in activated lung pericytes in our preliminary studies. We will examine how pericyte- derived ANGPTL4 affects lung endothelial function in this aim. In Aim 2, we will evaluate the role of lung pericytes in trafficking inflammatory monocytes. In murine models of influenza infection, inflammatory monocytes have been implicated in the development of lung injury. Recruitment of inflammatory monocytes in influenza occurs through a CC-chemokine receptor 2 (CCR2) dependent mechanism. Our work shows that activated pericytes highly upregulate CCL2, a major ligand for CCR2. We will evaluate the functional role of pericyte-derived CCL2, and other CCR2 ligands, in inflammatory monocyte recruitment. Finally, in Aim 3, we will characterize functional subsets in the pericyte population using single nucleus transcriptomic approaches. This proposed aim will provide insight into the diverse functional states of lung pericytes throughout the course of influenza infection and functional subtypes that mediate lung injury.

抽象的周细胞与肺损伤和许多器官的修复有关。肺基质亚群在组织损伤和修复中的作用，我们最近的工作揭示了肺周细胞来自活化肺的转录组分析的数据可能在损伤期间具有多种功能作用。周细胞揭示了参与炎症、血管生成和基质的多个基因的上调该项目的目标是表征周细胞反应的功能多样性。为了实现这一目标，我们将测试一种临床相关的肺损伤模型——流感感染。关于周细胞在内皮和免疫调节中的作用的假设在目标 1 中，我们将研究周细胞-内皮细胞串扰的机制导致内皮细胞活化并增加血管生成素-L4 (ANGPTL4) 被认为是一种通透性过高的因素。在我们的初步研究中，活化的肺周细胞也高度上调。在此目标中，衍生的 ANGPTL4 影响肺内皮功能，我们将评估肺的作用。在流感感染、炎症的小鼠模型中，周细胞运输炎症单核细胞。单核细胞与肺损伤的发生有关。炎症性单核细胞的募集。我们的工作表明，流感病毒是通过 CC 趋化因子受体 2 (CCR2) 依赖性机制发生的。激活的周细胞高度上调 CCL2（CCR2 的主要配体），我们将评估其功能。周细胞衍生的 CCL2 和其他 CCR2 配体在炎症单核细胞募集中的作用。目标 3，我们将使用单核转录组学来表征周细胞群中的功能子集这一提议的目标将深入了解肺周细胞的不同功能状态。整个流感感染过程和介导肺损伤的功能亚型。