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
基本信息
- 批准号:10701929
- 负责人:
- 金额:$ 42.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAddressAnti-Inflammatory AgentsCREB1 geneCellsCollaborationsCyclic AMP-Responsive DNA-Binding ProteinDataElectrophysiology (science)Gene DeletionHeterogeneityIndividualInflammasomeInflammationInflammatoryInflammatory ResponseInjuryInnate Immune ResponseIon ChannelIonsLeadLeftLigandsLungMacrophageMediatingMetabolicMicrobeModelingOncogenesPathway interactionsPatientsPhenotypePotassiumPotassium ChannelPurinoceptorRegulationResolutionRoleRous SarcomaSRC geneSTAT1 geneSTAT1 proteinSTAT6 Transcription FactorSTAT6 geneSignal PathwaySignal TransductionTestingTissuesTranscriptional Activationcalmodulin-dependent protein kinase IIextracellularinnate immune functioninward rectifier potassium channellung injurylung repairmeternoveloptogeneticsprogramspulmonary functionresponsesuccesstranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
Macrophages (Mφ) are essential for the innate immune function of lungs. The ability of macrophages to
integrate signals from microbes and the tissue niche and to polarize can either promote or resolve
inflammatory lung injury. Project 1 shows a fundamental role of the extracellular ATP (e[ATP]) activated- and
[Ca2+]in-sensitive cooperation between the purinergic receptor P2RX7 (Purinergic Receptor 2 subtype X7) and
potassium (K+) channel TWIK2 (Two-pore domain Weak Inwardly rectifying K+ channel 2) that is essential for
determining the macrophage phenotype. We show that e[ATP], the canonical P2RX7 ligand, governs Mφ
polarization through controlling [Ca2+]in and that activation of the TWIK2 K+ efflux channel induces the transition
to the pro-inflammatory state. We also observed that the TWIK2 response was itself dependent on the
activation of P2RX7 by e[ATP] and resultant Ca2+ influx. Thus, Project 1, we will investigate the interactions
between Ca2+ influx mediated by P2RX7 and its tuning of K+ efflux mediated by TWIK2, which we hypothesize
determines the transition to either pro-inflammatory Mφ (Inf-Mφ) or reparative Mφ (Rep-Mφ) fate via activation
of distinct downstream signaling pathways. This hypothesis will be tested by addressing the following Specific
Aims. Aim 1 will define respective mechanisms of P2RX7 and TWIK2 activation in mediating the shift in lung
macrophage polarity. Aim 2 will define the signaling pathways downstream of Mφ ion channels that promote
and resolve inflammatory lung injury. We posit that by identifying P2RX7 and TWIK2 activation and signaling
mechanisms responsible for macrophage phenotype switching, and by testing the role of P2RX7 in
coordinating the function of TWIK2 in the initial inflammatory response followed subsequent anti-inflammatory
response in Project 1, it will be possible to develop strategies to more effectively resolve inflammatory lung
injury and to make lung’s tolerance to injury through controlling macrophage polarization enhancing bacterial
killing function of MФ.
项目总结/摘要
巨噬细胞(Mφ)对肺的先天性免疫功能至关重要。巨噬细胞的能力
整合来自微生物和组织生态位的信号,
炎性肺损伤项目1显示了细胞外ATP(e[ATP])激活的基本作用,
[Ca2+]嘌呤能受体P2 RX 7(嘌呤能受体2亚型X7)和
钾(K+)通道TWIK 2(双孔结构域弱抑制整流K+通道2),对于
确定巨噬细胞表型。我们发现,典型的P2 RX 7配体e[ATP]支配Mφ
通过控制[Ca 2 +]in和激活TWIK 2 K+外排通道诱导了这种转变
到促炎状态我们还观察到TWIK 2反应本身依赖于
通过e[ATP]激活P2 RX 7并产生Ca 2+内流。因此,项目1,我们将研究
P2 RX 7介导的Ca 2+内流和TWIK 2介导的K+外流之间的关系,我们假设
通过激活决定向促炎性Mφ(Inf-Mφ)或修复性Mφ(Rep-Mφ)命运的转变
不同的下游信号通路。将通过解决以下具体问题来检验这一假设
目标。目的1将明确P2 RX 7和TWIK 2激活在介导肺转移中的各自机制,
巨噬细胞极性目的2将明确Mφ离子通道下游的信号通路,
解决炎症性肺损伤。我们通过鉴定P2 RX 7和TWIK 2的激活和信号传导,
负责巨噬细胞表型转换的机制,并通过测试P2 RX 7在
协调TWIK 2在最初的炎症反应中的功能,随后是抗炎反应。
在项目1中的反应,将有可能制定策略,以更有效地解决炎症肺
通过控制巨噬细胞极化增强细菌使肺对损伤产生耐受
杀鼠功能
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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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
- DOI:
10.1007/s00424-005-1461-z - 发表时间:
2005-06-30 - 期刊:
- 影响因子:2.900
- 作者:
Gias U. Ahmmed;Asrar B. Malik - 通讯作者:
Asrar B. Malik
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:
$ 42.55万 - 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:
$ 42.55万 - 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:
$ 42.55万 - 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:
$ 42.55万 - 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:
$ 42.55万 - 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:
$ 42.55万 - 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:
$ 42.55万 - 项目类别:
Macrophage Plasticity in Inflammatory Lung Injury
炎症性肺损伤中的巨噬细胞可塑性
- 批准号:
10491049 - 财政年份:2021
- 资助金额:
$ 42.55万 - 项目类别:
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