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

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.
抽象的 研究表明,内皮细胞通过调节流入和表型在宿主防御中发挥关键作用 免疫细胞。项目 3 重点描述线粒体功能障碍和线粒体自噬在内皮细胞中的作用 损伤期间调节肺血管稳态和宿主防御的细胞。拟议的研究将确定 EC 中线粒体损伤的机制以及适应性线粒体自噬如何激活补偿性线粒体 生物发生。项目 3 还将研究线粒体自噬和线粒体肽的释放如何影响中性粒细胞 在炎症性肺损伤期间。该提案将解决的基本问题包括: TNFα诱导线粒体损伤和线粒体自噬的机制是什么?我们可以使用线粒体生物传感器吗 体外和体内以确定线粒体自噬和补偿性线粒体生物发生的关键阶段?怎么样 内皮线粒体自噬影响内皮代谢恢复和内皮再生吗?怎么样 内皮线粒体自噬影响中性粒细胞信号传导、炎症损伤和宿主防御。项目3将测试 总体假设是肺内皮线粒体自噬是内皮稳态和先天性的中央调节器 免疫反应。这将在两个目标中得到解决。目标 1:确定内皮细胞线粒体自噬的作用和 补偿性线粒体生物发生以恢复内皮再生和稳态 炎症性肺损伤。在这里,我们将检验炎症诱导线粒体损伤的假设 肺内皮细胞的适应性线粒体自噬协调内皮再生和稳态。此外, 我们认为恢复体内平衡的核心机制是通过补偿性线粒体生物发生。 我们使用内皮线粒体自噬的活体双光子成像(使用 Core D)并使用 EC- 进行体内研究 线粒体自噬介体 PINK1(线粒体生物合成转录因子 PGC1α)的特异性基因缺失 和 TFAM,以及线粒体磷酸酶 PGAM5(将线粒体自噬后信号传递至细胞核) 对人肺 EC 进行机械驱动的体外研究。这些研究将与 EC 分析相结合 代谢、线粒体生物合成和 EC 再生。目标 2:确定内皮线粒体自噬的作用 在炎症损伤期间激活肺宿主防御功能。在这里我们将检验以下假设: EC-线粒体自噬增加跨内皮中性粒细胞流入,从而通过分泌 甲酰化肽和甲酰肽受体的激活。我们将使用 EC 特异性 PINK1 的遗传模型 不同炎症性肺损伤模型(LPS 和假单胞菌肺炎)中的缺失并分析 EC 线粒体自噬引起的表观遗传和转录组调控(核心 B)并解决了这些调控如何促进线粒体自噬 EC 和 EC PINK1 下游中性粒细胞的宿主防御功能。我们还将评估 EC-PINK1 如何监管 中性粒细胞诱导的肺损伤和 N-甲酰化线粒体肽的产生。我们还将确定 肺 EC 线粒体自噬对中性粒细胞迁移和细菌吞噬作用的影响(核心 D)并研究 中性粒细胞中线粒体甲酰基肽下游的信号通路(具有核心 C)。

项目成果

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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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