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CREB Instruction of Macrophage Fate and Lung fluid homeostasis

CREB对巨噬细胞命运和肺液稳态的指导

基本信息

批准号：
10625859
负责人：
DOLLY MEHTA
金额：
$ 15.99万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2021-09-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625859
关键词：
ATAC-seq Acetyl Coenzyme A Acute Lung Injury Acute Respiratory Distress Syndrome Alveolar Alveolar Macrophages BACH2 gene Binding Biological Assay Cell Nucleus ChIP-seq Chromatin Critical Illness Cyclic AMP Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein Data Development Disease Endothelium Epigenetic Process Epithelium Exhibits Extravasation Fluid Balance Gene Expression Generations Genes Genetic Genetic Transcription Histone Acetylation Homeostasis ITGAM gene ITGAX gene Immune Impairment Inflammatory Inflammatory Response Injury Instruction Leukocytes Life Lung Lung Capacity Macrophage Mitochondria Mus Myeloid Cells Nuclear Pathway interactions Patients Plasma Population Production Pseudomonas aeruginosa infection Pyruvate Dehydrogenase Complex Recovery Regulation Regulatory Element Research Role Sentinel Signal Induction Signal Pathway Sorting Source Testing Therapeutic Tissues Transposase Vascular Permeabilities cell type chromatin remodeling cytokine histone modification injury and repair insight interstitial lung injury lung repair lung vascular injury monocyte mortality multiple omics novel novel therapeutic intervention pharmacologic prevent programs promoter protein expression pyruvate dehydrogenase kinase 4 repair strategy restoration single-cell RNA sequencing tissue injury tissue repair transcription factor transcriptome sequencing vascular injury

项目摘要

Abstract Recovery from severe forms of inflammatory vascular injury, such as acute lung injury (ALI), depends on the lung's capacity to rapidly activate tissue repair pathways. Macrophages (Mφ), the most abundant sentinel immune cell type in the lung, are required for restoration of tissue-fluid homeostasis following injury, but the identity of the reparative Mφ subpopulations and how they are generated remain elusive. Here, we have discovered a subset of the alveolar Mφ (AMφ) population that is required to maintain lung fluid homeostasis basally and induce tissue repair after injury. Our Supporting Data show that: 1) loss of cAMP Response Element Binding (CREB) protein expression in myeloid cells (Creb∆LyzM mice) arrest a subpopulation of the AMφ lineage at the pre-AMφ stage, leading to decreased AMφ generation and increased lung vascular permeability basally; 2) Creb∆LyzM mice failed to resolve injury post-LPS challenge and died more rapidly after Pseudomonas aeruginosa infection; 3) transcriptome sequencing (RNAseq) and chromatin accessibility profiling (ATACseq) of flow-sorted CREB-null AMφ have markedly altered gene expression and chromatin remodeling; and 4) CREB is required to inhibit excessive production of nuclear acetyl-CoA from the pyruvate dehydrogenase complex (PDC) through synthesis of pyruvate dehydrogenase kinase 4 (PDK4). Based on these provocative Preliminary Data, in Aim#1, we will test the hypothesis that CREB transcriptionally promotes differentiation of this barrier reparative AMφ subpopulation. In Aim#2, we will investigate that CREB regulates reparative AMφ generation by controlling epigenetic modifications of histones thereby leading to AMφ gene transcription. Here, we will address the novel concept that the transcriptional activity of CREB is required to upregulate PDK4 expression, which in turn prevents transport of its target, PDC, from mitochondria to the nucleus thereby suppressing excessive nuclear acetyl Co-A generation and limiting epigenetic modifications of histones, leading to gene transcription that induces the barrier reparative AMφ population. These studies will employ a rigorous multi- omics approach (single-cell RNA-, ATAC-and Chip-sequencing) and functional assays in genetically altered mice including Rosa-CrebCxcxr3-ERT mice (in which CREB is conditionally deleted in monocytes/interstitial macrophages) to define the role of CREB transcriptional activity in generating the reparative AMφ population. Understanding how this barrier reparative AMɸ subset is generated should make it possible to enhance differentiation of this subset during injury by pharmacological or genetic means, thereby reducing the mortality of ALI and related conditions.

摘要