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:
- 金额:$ 44.37万
- 依托单位:
- 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:
- 关键词:AcuteAddressAffectBacterial ProteinsBindingBiogenesisBiosensorBlood VesselsBrainCardiovascular DiseasesCell DeathCell NucleusCellsCellular Metabolic ProcessChronic DiseaseCoupledDataDisease OutcomeElectron TransportEndothelial CellsEndotheliumEnzymesEpigenetic ProcessEquilibriumFunctional disorderGene Expression ProfileGenerationsGenesGeneticGenetic InductionGenetic ModelsHeartHomeostasisHost DefenseHumanImageImmuneIn VitroIndividualInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryInnate Immune ResponseInnate Immune SystemInstructionInterferon Type IKnock-outLeukocytesLungMammalian CellMediator of activation proteinMetabolismMethionineMitochondriaMitochondrial DNAMitochondrial ProteinsModelingMolecularMusNatural regenerationNuclearNuclear ProteinsOxidesPINK1 geneParacrine CommunicationParkinPatternPeptidesPhagocytosisPhasePhenotypePhosphoric Monoester HydrolasesPhosphotransferasesPlayPneumoniaProductionProtein KinaseProteinsPseudomonasReactive Oxygen SpeciesRegulationRegulator GenesRoleSignal PathwaySignal TransductionSiteT-LymphocyteTNF geneTestingTranslationsUbiquitinationbeta catenincell regenerationchemokinecytokineendothelial regenerationfMet-Leu-Phe receptorformyl peptidein vivolung injurymitochondrial autophagymitochondrial dysfunctionneutrophilrecruitresponserestorationtranscription factortranscriptomicstranslatometwo-photonubiquitin ligasevascular 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jalees Rehman其他文献
Jalees Rehman的其他文献
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{{ truncateString('Jalees Rehman', 18)}}的其他基金
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
- 批准号:
10706520 - 财政年份:2022
- 资助金额:
$ 44.37万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 44.37万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 44.37万 - 项目类别:
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:
10701931 - 财政年份:2021
- 资助金额:
$ 44.37万 - 项目类别:
Integration Free IPS Cells-Derived Progenitors for Cardiac Regeneration
用于心脏再生的免整合 IPS 细胞衍生祖细胞
- 批准号:
9441040 - 财政年份:2015
- 资助金额:
$ 44.37万 - 项目类别:
Integration Free IPS Cells-Derived Progenitors for Cardiac Regeneration
用于心脏再生的免整合 IPS 细胞衍生祖细胞
- 批准号:
9226014 - 财政年份:2015
- 资助金额:
$ 44.37万 - 项目类别:
The role of mitochondria in embryonic stem cells.
线粒体在胚胎干细胞中的作用。
- 批准号:
8323300 - 财政年份:2011
- 资助金额:
$ 44.37万 - 项目类别:
The role of mitochondria in embryonic stem cells.
线粒体在胚胎干细胞中的作用。
- 批准号:
8653967 - 财政年份:2011
- 资助金额:
$ 44.37万 - 项目类别:
The role of mitochondria in embryonic stem cells.
线粒体在胚胎干细胞中的作用。
- 批准号:
8108690 - 财政年份:2011
- 资助金额:
$ 44.37万 - 项目类别:
The role of mitochondria in embryonic stem cells.
线粒体在胚胎干细胞中的作用。
- 批准号:
8463217 - 财政年份:2011
- 资助金额:
$ 44.37万 - 项目类别:
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