Endothelial Instruction of Macrophage Fate in Inflammatory Lung Injury

炎症性肺损伤中巨噬细胞命运的内皮指令

• 批准号: 10491076
• 负责人: Jalees Rehman
• 金额: $ 42.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491076
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acute Lung Injury; Address; Adult; Alveolar Macrophages; Anti-Inflammatory Agents; Binding; Blood Vessels; Cell Line; Cell Nucleus; Cells; Characteristics; Collaborations; Complex; Data; Endothelial Cells; Endothelium; Enzymes; Epigenetic Process; G-Protein-Coupled Receptors; Generations; Genetic Transcription; Histone Acetylation; Homeostasis; Human; ITGAM gene; Image; Immune; In Vitro; Individual; Inflammation; Inflammatory; Injury; Instruction; Leucine-Rich Repeat; Licensing; Life; Lipoprotein Receptor; LoxP-flanked allele; Lung; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Mus; NADH; Patients; Phenotype; Population; Process; Proteins; Regulation; Resolution; Respiration; Role; Signal Transduction; Testing; Tissues; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; WNT Signaling Pathway; beta catenin; cell type; epigenetic regulation; epigenome; high resolution imaging; in vivo; interstitial; lung injury; macrophage; metabolomics; mitochondrial metabolism; monocyte; mouse model; optogenetics; prenatal; programs; receptor; response to injury; single-cell RNA sequencing; synthetic biology; tissue injury; tissue repair; transcriptomics

PROJECT SUMMARY/ABSTRACT Studies have shown much broader roles for macrophages in responding to inflammation and tissue injury than previously recognized, such as promoting inflammation resolution, tissue repair and restoring tissue homeostasis and this recognition of macrophage plasticity has shifted the focus away from the simple notion of M1 and M2 dichotomies. Project 3 focuses on delineating the signals mediating monocyte transition to tissue macrophages and their potentially essential role in tissue repair in acute lung injury (ALI). As the lung endothelium is the entry point of the monocytes transmigrating into tissue, endothelial cells (ECs) may modify the downstream macrophage phenotype, and thus the interaction between cells may be of great consequence. Project 3 will delineate mechanisms of generation of how ECs instruct macrophages and their role in resolving ALI. We will address fundamental questions including: What are the EC signals mediating transition to the reparative macrophage populations? What signals in macrophages in turn convert the cells to repair tissue? What are the epigenetic and transcriptomic features of these phenotype-shifted macrophages? In Project 3 we will test the hypothesis that the lung endothelium via Wnt signaling mediates macrophage phenotype transition through modifying mitochondrial metabolism and epigenome that initiates specific transcriptional programs. In Aim 1, we will define the role of endothelial Wnt signaling in regulating the differentiation of monocytes to macrophages in lungs. Here we will determine the role of the Wnt signaling regulator Rspondin 3 (Rspo3) derived from ECs in signaling the transition of monocytes to lung macrophages. In Aim 2, we will determine the role of metabolic reprogramming and epigenetic modifications of macrophages in mediating phenotype transition and thereby reducing the extent of lung injury as well as promoting its resolution.

项目摘要/摘要 研究表明，巨噬细胞在应对炎症和组织损伤方面的作用比 先前公认的，如促进炎症消退、组织修复和恢复组织内稳态 这种对巨噬细胞可塑性的认识转移了人们对M1和M2的简单概念的关注 一分为二。项目3的重点是描述单核细胞向组织巨噬细胞转化的信号。 它们在急性肺损伤(ALI)的组织修复中具有潜在的重要作用。因为肺内皮细胞是 单核细胞向组织内迁移，内皮细胞(ECs)可修饰下游巨噬细胞 表型，因此细胞之间的相互作用可能是很重要的结果。项目3将描绘 内皮细胞指令巨噬细胞的发生机制及其在解决ALI中的作用。我们将解决 基本问题包括：介导向修复性巨噬细胞转变的EC信号是什么 人口？巨噬细胞中的哪些信号反过来将细胞转化为修复组织？什么是表观遗传学和 这些表型转变的巨噬细胞的转录特征？在项目3中，我们将测试假设 肺内皮细胞通过Wnt信号修饰线粒体介导巨噬细胞表型转化 启动特定转录程序的新陈代谢和表观基因组。在目标1中，我们将定义 内皮细胞Wnt信号调节肺内单核细胞向巨噬细胞分化。在这里，我们将 确定来源于内皮细胞的Wnt信号调节因子响应素3(Rsp3)在信号转导中的作用 单核细胞转化为肺巨噬细胞。在目标2中，我们将确定代谢重新编程和表观遗传学的作用 巨噬细胞在介导表型转换中的修饰，从而减轻AS肺损伤的程度 以及推动其解决方案。