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Mitochondrial Dysfunction in the Endothelium as a Mediator of Inflammatory Injury

内皮细胞线粒体功能障碍是炎症损伤的介质

基本信息

批准号：
10494618
负责人：
Jalees Rehman
金额：
$ 44.37万
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：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10494618
关键词：
Acute Address Affect Bacterial Proteins Binding Biogenesis Biosensor Blood Vessels Brain Cardiovascular Diseases Cell Death Cell Nucleus Cells Cellular Metabolic Process Chronic Disease Coupled Data Disease Outcome Electron Transport Endothelial Cells Endothelium Enzymes Epigenetic Process Equilibrium Functional disorder Gene Expression Profile Generations Genes Genetic Genetic Induction Genetic Models Heart Homeostasis Host Defense Human Image Immune In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Instruction Interferon Type I Knock-out Leukocytes Lung Mammalian Cell Mediator of activation protein Metabolism Methionine Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Molecular Mus Natural regeneration Nuclear Nuclear Proteins Oxides PINK1 gene Paracrine Communication Parkin Pattern Peptides Phagocytosis Phase Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Play Pneumonia Production Protein Kinase Proteins Pseudomonas Reactive Oxygen Species Regulation Regulator Genes Role Signal Pathway Signal Transduction Site T-Lymphocyte TNF gene Testing Translations Ubiquitination beta catenin cell regeneration chemokine cytokine endothelial regeneration fMet-Leu-Phe receptor formyl peptide in vivo lung injury mitochondrial autophagy mitochondrial dysfunction neutrophil recruit response restoration transcription factor transcriptomics translatome two-photon ubiquitin ligase vascular injury

项目摘要

ABSTRACT Studies have shown that the endothelium plays a critical role in host defense by regulating the influx and phenotype of immune cells. Project 3 focuses on delineating the role of mitochondrial dysfunction and mitophagy in endothelial cells in regulating lung vascular homeostasis and host-defense during injury. The proposed studies will identify mechanisms of mitochondrial injury in ECs as well as how adaptive mitophagy activates compensatory mitochondrial biogenesis. Project 3 will also examine how mitophagy and the release of mitochondrial peptides impact neutrophils during inflammatory lung injury. The fundamental questions that will be addressed by this proposal include: What are the mechanisms of TNFα induced mitochondrial injury and mitophagy? Can we use biosensors for mitochondria in vitro and in vivo to define key phases of mitophagy and compensatory mitochondrial biogenesis? How does endothelial mitophagy affect restoration of endothelial metabolism and endothelial regeneration? How does endothelial mitophagy impact neutrophil signaling, inflammatory injury and host defense. Project 3 will test the overall hypothesis that lung endothelial mitophagy is a central regulator of endothelial homeostasis and the innate immune response. This will be addressed in two Aims. Aim 1: Determine the role of endothelial mitophagy and compensatory mitochondrial biogenesis to restore endothelial regeneration and homeostasis during inflammatory lung injury. Here we will test the hypothesis that inflammation induces mitochondrial injury and adaptive mitophagy in the lung endothelium to orchestrate endothelial regeneration and homeostasis. Furthermore, we posit that the central mechanism of restoring homeostasis is through the compensatory mitochondrial biogenesis. We use intravital two photon imaging of endothelial mitophagy (with Core D) and perform in vivo studies using EC- specific genetic deletion of the mitophagy mediator PINK1, the mitochondrial biogenesis transcription factors PGC1α and TFAM, and the mitochondrial phosphatase PGAM5 (which transfers post-mitophagy signaling to the nucleus) with mechanistically driven in vitro studies in human lung ECs. These studies will be coupled to analysis of EC metabolism, mitochondrial biogenesis, and EC regeneration. Aim 2: Determine the role of endothelial mitophagy in activating the lung host-defense function during inflammatory injury. Here we will test the hypothesis that EC-mitophagy increases transendothelial neutrophil influx and thereby bacterial killing through secretion of formylated peptides and activation of formyl peptide receptors. We will use genetic models of EC-specific PINK1 deletion in distinct models of inflammatory lung injury (LPS and Pseudomonas pneumonia) and analyze EC epigenetic and transcriptomic regulation (with Core B) wrought by mitophagy and address how these contribute to host-defense function of EC and neutrophils downstream of EC PINK1. We will also assess how EC-PINK1 regulates neutrophil-induced lung injury and generation of N-formylated mitochondrial peptides. We will also determine the effects of lung EC mitophagy on neutrophil transmigration and bacterial phagocytosis (with Core D) and study the signaling pathways (with Core C) downstream of mitochondrial formyl peptides in neutrophils.

摘要