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: 10170865
• 负责人: Jalees Rehman
• 金额: $ 30.14万
• 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/10170865
• 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要比 先前已识别的，例如促进炎症分辨率，组织修复和恢复组织稳态 对巨噬细胞可塑性的这种认识使焦点从M1和M2的简单概念转移了 二分法。项目3的重点是描述介导单核细胞过渡到组织巨噬细胞的信号和 它们在组织修复中的潜在至关重要的作用在急性肺损伤（ALI）中。因为肺内皮是 单核细胞转移到组织，内皮细胞（EC）可能会改变下游巨噬细胞 表型，因此细胞之间的相互作用可能是很大的结果。项目3将描绘 ECS如何指导巨噬细胞及其在解决Ali中的作用的机制。我们将解决 基本问题，包括：EC信号介导向修复巨噬细胞的过渡是什么 人口？巨噬细胞中的哪些信号反过来将细胞转换为修复组织？什么是表观遗传和 这些表型变为巨噬细胞的转录组特征？在项目3中，我们将检验以下假设 通过Wnt信号传导肺内皮介导巨噬细胞表型通过修饰线粒体的转变 启动特定转录程序的代谢和表观基因组。在AIM 1中，我们将定义 在调节单核细胞与肺中巨噬细胞的分化时，内皮Wnt信号传导。我们会在这里 确定Wnt信号调节剂Rspondin 3（RSPO3）在ECS信号中得出的作用 单核细胞到肺巨噬细胞。在AIM 2中，我们将确定代谢重编程和表观遗传的作用 巨噬细胞在介导表型转变中的修饰，从而减少肺损伤程度 以及促进其解决方案。