MAM Proteins in Lung Vascular Injury

MAM 蛋白在肺血管损伤中的作用

基本信息

  • 批准号:
    10680808
  • 负责人:
  • 金额:
    $ 69.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition which affects ~200,000 Americans each year with 10-15% of intensive care admissions and a mortality rate of ~ 25-40%. Sepsis is a prominent extrapulmonary cause of ALI in humans. Nearly 50% of patients with severe sepsis develop ALI/ARDS. All current therapies for ALI/ARDS still rely on supportive care; thus, there is an urgent need to develop new treatment strategies for ALI/ARDS that are safe and effective. Because endothelial cell (EC) barrier dysfunction is an early and critical component of ALI in sepsis, a better understanding of the mechanisms of EC permeability is key to developing effective therapy for ALI. The goal of this proposal is to understand how aberrant communication between endoplasmic reticulum (ER) and mitochondrion in sepsis, mediated by ER chaperone BiP/GRP78 and mitochondrial (MITO) chaperone Mortalin/GRP75, promotes EC barrier dysfunction to cause ALI. Our hypothesis is that a close interaction and functional cooperation between BiP/GRP78 and Mortalin/GRP75 at the MAMs (mitochondrial associated endoplasmic reticulum membranes) serves to increase cytosolic Ca2+ and ER-MITO contact sites to cause mitochondrial Ca2+ overload and inflammasome activation, leading to lung vascular injury in sepsis. We further hypothesize that targeting BiP/GRP78 and Mortalin/GRP75 in combination may prove a superior therapeutic approach against sepsis-induced ALI and mortality. The proposal is based on our novel findings that BiP/GRP78 and Mortalin/GRP75 are key regulators of Ca2+ signaling and ER-MITO contact sites in EC and silencing BiP/GRP78 or Mortalin/GRP75 each prevents EC barrier disruption caused by plasma from septic patients and other clinically relevant edemagenic agonists such as thrombin and LPS. BiP/GRP78 is induced in septic lung and overexpressing BiP/GRP78 in the resting lung endothelium is sufficient to cause lung injury in mice. Moreover, inhibiting BiP/GRP78 or Mortalin/GRP75 each mitigates ALI in mice. Importantly, combined inhibition of BiP/GRP78 or Mortalin/GRP75 is far more effective (requires ~5-fold less dose of BiP/GRP78 or Mortalin/GRP75 inhibitors) in improving survival in mice with sepsis. The proposal will address the following aims. Aim 1 will determine the role of BiP/GRP78 and Mortalin/GRP75 in regulating cytosolic Ca2+ to cause EC permeability. Aim 2 will determine the role of BiP/GRP78 and Mortalin/GRP75 in increasing ER-MITO contact sites and mitochondrial Ca2+ uptake to cause mitochondrial dysfunction and inflammasome activation leading to EC permeability. Aim 3 will determine (i) the contribution of endothelial BiP/GRP78 and Mortalin/GRP75 in causing lung injury, and (ii) assess the therapeutic potential of inhibiting BiP/GRP78 and Mortalin/GRP75 together against sepsis-induced ALI and mortality. These studies will provide valuable insight into the ER-MITO communication and its relevance in the pathogenesis of ALI and may lead to development of a safe and efficacious therapeutic strategy that relies on combined inhibition of BiP/GRP78 and Mortalin/GRP75 to control ALI and improve survival in sepsis.
急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是一种危及生命的疾病, 每年约有20万美国人,重症监护入院率为10-15%,死亡率约为25- 40%。 脓毒症是人类ALI的主要肺外原因。近50%的严重脓毒症患者 发生ALI/ARDS。目前所有的ALI/ARDS治疗仍然依赖于支持性护理,因此,迫切需要 开发安全有效的治疗ALI/ARDS的新策略。因为内皮细胞(EC) 屏障功能障碍是脓毒症ALI的早期和关键组成部分, EC通透性的降低是开发有效治疗ALI的关键。本提案的目标是了解如何 脓毒症中内质网(ER)介导的内质网和内质网蛋白(Ep)之间的异常通讯 伴侣BiP/GRP 78和线粒体(MITO)伴侣Mortalin/GRP 75促进EC屏障功能障碍 导致ALI我们的假设是BiP/GRP 78和GRP之间的密切相互作用和功能合作。 MAMs(线粒体相关内质网膜)上的Mortalin/GRP 75用于增加 胞质Ca 2+和ER-MITO接触位点引起线粒体Ca 2+过载和炎性小体活化, 导致败血症中的肺血管损伤。我们进一步假设,靶向BiP/GRP 78和Mortalin/GRP 75, 联合使用可能证明是对抗脓毒症诱导ALI和死亡率的上级治疗方法。的 我们的新发现是BiP/GRP 78和Mortalin/GRP 75是Ca 2+信号的关键调节因子 并且沉默BiP/GRP 78或Mortalin/GRP 75各自防止EC屏障 由脓毒症患者的血浆和其他临床相关的水肿激动剂引起的破坏, 凝血酶和LPS。BiP/GRP 78在脓毒症肺中被诱导并且在静息肺中过表达BiP/GRP 78 内皮细胞足以引起小鼠肺损伤。此外,抑制BiP/GRP 78或Mortalin/GRP 75各自 减轻小鼠的ALI。重要的是,BiP/GRP 78或Mortalin/GRP 75的组合抑制远更有效 (需要约5倍更少剂量的BiP/GRP 78或Mortalin/GRP 75抑制剂)改善脓毒症小鼠的存活率。 该提案将针对以下目标。目的1将确定BiP/GRP 78和Mortalin/GRP 75的作用 调节胞浆Ca ~(2+)引起EC通透性。目标2将确定BiP/GRP 78的作用, Mortalin/GRP 75在增加ER-MITO接触位点和线粒体Ca 2+摄取以引起线粒体Ca 2+摄取中的作用 功能障碍和炎性体活化导致EC渗透性。目标3将确定(一) 内皮BiP/GRP 78和Mortalin/GRP 75在引起肺损伤中的作用,以及(ii)评估BiP/GRP 78和Mortalin/GRP 75的治疗潜力。 共同抑制BiP/GRP 78和Mortalin/GRP 75可对抗脓毒症诱导的ALI和死亡率。这些研究将 为ER-MITO通讯及其在ALI发病机制中的相关性提供了有价值的见解, 导致开发了一种安全有效的治疗策略, BiP/GRP 78和Mortalin/GRP 75用于控制ALI并改善脓毒症中的存活。

项目成果

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Fabeha Fazal其他文献

Fabeha Fazal的其他文献

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{{ truncateString('Fabeha Fazal', 18)}}的其他基金

Regulation of Endothelial-Neutrophil Interaction and Lung Vascular Permeability in Sepsis
脓毒症中内皮-中性粒细胞相互作用和肺血管通透性的调节
  • 批准号:
    9788499
  • 财政年份:
    2018
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial-Neutrophil Interaction and Lung Vascular Permeability in Sepsis
脓毒症中内皮-中性粒细胞相互作用和肺血管通透性的调节
  • 批准号:
    10004113
  • 财政年份:
    2018
  • 资助金额:
    $ 69.49万
  • 项目类别:
ER-Mitochondrial Control of Acute Lung Injury
ER-线粒体对急性肺损伤的控制
  • 批准号:
    9173789
  • 财政年份:
    2016
  • 资助金额:
    $ 69.49万
  • 项目类别:
ER-Mitochondrial Control of Acute Lung Injury
ER-线粒体对急性肺损伤的控制
  • 批准号:
    9328149
  • 财政年份:
    2016
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial ICAM-1 and PMN-Mediated Lung Injury by Actin Dynamics
肌动蛋白动力学对内皮 ICAM-1 和 PMN 介导的肺损伤的调节
  • 批准号:
    7887122
  • 财政年份:
    2010
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial ICAM-1 and PMN-Mediated Lung Injury by Actin Dynamics
肌动蛋白动力学对内皮 ICAM-1 和 PMN 介导的肺损伤的调节
  • 批准号:
    8051760
  • 财政年份:
    2010
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial ICAM-1 and PMN-Mediated Lung Injury by Actin Dynamics
肌动蛋白动力学对内皮 ICAM-1 和 PMN 介导的肺损伤的调节
  • 批准号:
    8235015
  • 财政年份:
    2010
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial ICAM-1 and PMN-Mediated Lung Injury by Actin Dynamics
肌动蛋白动力学对内皮 ICAM-1 和 PMN 介导的肺损伤的调节
  • 批准号:
    8646963
  • 财政年份:
    2010
  • 资助金额:
    $ 69.49万
  • 项目类别:
Regulation of Endothelial ICAM-1 and PMN-Mediated Lung Injury by Actin Dynamics
肌动蛋白动力学对内皮 ICAM-1 和 PMN 介导的肺损伤的调节
  • 批准号:
    8446994
  • 财政年份:
    2010
  • 资助金额:
    $ 69.49万
  • 项目类别:
MLC Dephosphorylation in Smooth Muscle Cell Apoptosis
平滑肌细胞凋亡中的 MLC 去磷酸化
  • 批准号:
    6486367
  • 财政年份:
    2002
  • 资助金额:
    $ 69.49万
  • 项目类别:

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