Trpm2 Regulation of Phagocyte Bactericidal Activity and Resolution of Lung Injury

Trpm2 对吞噬细胞杀菌活性的调节和肺损伤的解决

基本信息

  • 批准号:
    9111056
  • 负责人:
  • 金额:
    $ 41.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-08-01 至
  • 项目状态:
    未结题

项目摘要

Project Summary The efficiency of bacterial killing by alveolar macrophages (AMФ) is an essential determinant of the lung's ability to resolve inflammatory lung injury, and indeed may be required for the development of tolerance to lung injury induced by secondary infection. However, the molecular mechanisms of bacterial killing are not well understood. The crucial observation underpinning Project 1 shows a fundamental host-defense function of the ROS-sensitive transient receptor potential melastatin-2, TRPM2, a phagosomal membrane-associated cation channel, in regulating bactericidal activity of MФ. TRPM2 was essential for controlling the pH of phagosomes and blocking of the TRPM2-mediated acidification prevented bacterial killing and, moreover, enhanced inflammatory lung injury. Thus, in Project 1 we will test the central hypothesis that phagosome-associated TRPM2 in MФ promotes the resolution of inflammatory lung injury by regulating phagosomal acidification, and thereby is a central mechanism for activating bacterial killing. This hypothesis will be tested by addressing the following Specific Aims (SA). SA #1 will determine the role of phagosomal membrane TRPM2 activation induced by the oxidases NOX2 and/or NOX4 in regulating the phagosomal acidification property of MФ, and thus in generating bactericidal-competent MФ. SA #2 will define the crucial TRPM2-regulated negative feedback mechanism in MФ that may also acidify phagosomes through dampening NOX2/NOX4-mediated ROS production, and thus the promote bacteria killing function of MФ. SA #3 will determine the role of TRPM2 regulated phagosomal acidification in resolving inflammatory lung injury using genetically modified models with specific deletion of TRPM2 in phagocytic cells, and the role enhanced phagosomal acidification in promoting the tolerance to injury induced by secondary infection. We posit that by identifying the central signaling mechanisms responsible for TRPM2 activation in the MФ phagosomes, it will be possible to develop strategies to more effectively resolve inflammatory lung injury and to make lung's tolerance to injury through enhancing bacterial killing function of MФ.
项目摘要 肺泡巨噬细胞(AM-Ф)对细菌的杀灭效率是决定肺功能的重要因素 解决炎症性肺损伤的能力,确实可能是发展对肺的耐受性所必需的 继发感染所致的损伤。然而,细菌杀灭的分子机制还不是很清楚。 明白了。支撑项目1的关键观测显示了 吞噬体膜相关阳离子--ROS敏感的瞬时受体电位-2,TRPM2 通道,调节M-Ф的杀菌活性。TRPM2对控制吞噬小体的pH是必不可少的 阻断TRPM2介导的酸化阻止了细菌的杀灭,而且增强了 炎症性肺损伤。因此,在项目1中,我们将检验与吞噬小体相关的中心假设 M-Ф中的TRPM2通过调节吞噬促进炎性肺损伤的消退 酸化,因此是激活细菌杀灭的中心机制。这一假设将是 通过解决以下特定目标(SA)进行测试。SA#1将决定吞噬小体的作用 氧化酶NOX2和/或NOX4在调节吞噬小体中诱导的膜TRPM2激活 MФ的酸化特性,从而产生杀菌能力强的MФ。SA#2将定义关键的 TRPM2调节M-Ф的负反馈机制也可能通过抑制来酸化吞噬小体 NOX2/NOX4介导ROS的产生,从而促进M-Ф的杀菌作用。SA#3将 确定TRPM2调节的吞噬体酸化在减轻炎性肺损伤中的作用 在吞噬细胞中特异性缺失TRPM2的转基因模型及其作用增强 吞噬体酸化在提高对继发感染损伤耐受性中的作用我们假设,通过 确定负责MФ吞噬体内TRPM2激活的中央信号机制,它将 有可能制定更有效地解决炎症性肺损伤的策略,并使肺的 通过增强M-Ф的杀菌功能来耐受伤害。

项目成果

期刊论文数量(0)
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Asrar B. Malik其他文献

Tissue Regeneration Requires Edema Fluid Clearance by Compensatory Lymphangiogenesis in Zebrafish
斑马鱼的组织再生需要通过补偿性淋巴管生成清除水肿液
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Olamide Olayinka;Hannah Ryu;Xiaowei Wang;Asrar B. Malik;Hyun Min Jung
  • 通讯作者:
    Hyun Min Jung
H<sub>2</sub>O<sub>2</sub> and Tumor Necrosis Factor-α Activate Intercellular Adhesion Molecule 1 (ICAM-1) Gene Transcription through Distinct <em>cis</em>-Regulatory Elements within the ICAM-1 Promoter
  • DOI:
    10.1074/jbc.270.32.18966
  • 发表时间:
    1995-08-11
  • 期刊:
  • 影响因子:
  • 作者:
    Kenneth A. Roebuck;Arshad Rahman;Venkatesh Lakshminarayanan;Kilambi Janakidevi;Asrar B. Malik
  • 通讯作者:
    Asrar B. Malik
Functional role of TRPC channels in the regulation of endothelial permeability
Compensatory lymphangiogenesis is required for edema resolution in zebrafish
补偿性淋巴管生成是斑马鱼水肿消退所必需的
  • DOI:
    10.1038/s41598-025-92970-1
  • 发表时间:
    2025-03-10
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Olamide Olayinka;Hannah Ryu;Xiaowei Wang;Asrar B. Malik;Hyun Min Jung
  • 通讯作者:
    Hyun Min Jung
The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury
GTPase Rab1 是 NLRP3 炎症小体激活和炎症性肺损伤所必需的
  • DOI:
    10.4049/jimmunol.1800777
  • 发表时间:
    2018-11
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Yuehui Zhang;Lijun Wang;Yang Lv;Chunling Jiang;Guangyu Wu;R;al O. Dull;Richard D. Minshall;Asrar B. Malik;Guochang Hu
  • 通讯作者:
    Guochang Hu

Asrar B. Malik的其他文献

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{{ truncateString('Asrar B. Malik', 18)}}的其他基金

iPSC-Derived Vascularized Human Lung Organoids and Interaction Between Lung Endothelial Cells and Alveolar Epithelial Cells
iPSC 衍生的血管化人肺类器官以及肺内皮细胞和肺泡上皮细胞之间的相互作用
  • 批准号:
    10467249
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
Mechanisms and Treatment of SARS-CoV-2 induced Lung Endothelial Injury
SARS-CoV-2引起的肺内皮损伤的机制和治疗
  • 批准号:
    10559640
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
iPSC-Derived Vascularized Human Lung Organoids and Interaction Between Lung Endothelial Cells and Alveolar Epithelial Cells
iPSC 衍生的血管化人肺类器官以及肺内皮细胞和肺泡上皮细胞之间的相互作用
  • 批准号:
    10673199
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
E3 Ubiquitin Ligase CHFR Regulates Lung Endothelial Barrier Integrity and Innate Immunity through Control of VE-cadherin Expression
E3 泛素连接酶 CHFR 通过控制 VE-钙粘蛋白表达来调节肺内皮屏障完整性和先天免疫
  • 批准号:
    10706515
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
E3 Ubiquitin Ligase CHFR Regulates Lung Endothelial Barrier Integrity and Innate Immunity through Control of VE-cadherin Expression
E3 泛素连接酶 CHFR 通过控制 VE-钙粘蛋白表达来调节肺内皮屏障完整性和先天免疫
  • 批准号:
    10494617
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
Mechanisms and Treatment of SARS-CoV-2 induced Lung Endothelial Injury
SARS-CoV-2引起的肺内皮损伤的机制和治疗
  • 批准号:
    10390863
  • 财政年份:
    2022
  • 资助金额:
    $ 41.09万
  • 项目类别:
Amplification Mechanisms of Lung Endothelial Inflammation During Acute Lung Injury
急性肺损伤期间肺内皮炎症的放大机制
  • 批准号:
    10435435
  • 财政年份:
    2021
  • 资助金额:
    $ 41.09万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10491051
  • 财政年份:
    2021
  • 资助金额:
    $ 41.09万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10701924
  • 财政年份:
    2021
  • 资助金额:
    $ 41.09万
  • 项目类别:
Ion Flux Regulation of Macrophage Plasticity in Lung Injury and Repair
肺损伤与修复中巨噬细胞可塑性的离子通量调节
  • 批准号:
    10701929
  • 财政年份:
    2021
  • 资助金额:
    $ 41.09万
  • 项目类别:

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