Resistin regulates NLRP3 inflammasome in pulmonary hypertension

抵抗素调节肺动脉高压中的 NLRP3 炎性体

基本信息

  • 批准号:
    10567914
  • 负责人:
  • 金额:
    $ 70.15万
  • 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:
    2023-08-10 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Extensive work has implicated human resistin (Hresistin) and its rodent correlate resistin-like molecule (RELM)- α in inflammatory mechanisms of pulmonary hypertension (PH). Elevated levels of Hresistin in the lungs of idiopathic PAH and Scleroderma PH patients1,2 correlate with the disease severity of PH and predict mortality.3 Rodent models of PH show RELMα is critical to PH remodeling of the lung vasculature and right heart.3-7 We reported Bruton’s Tyrosine Kinase (BTK) as a binding partner of RELMα/Hresistin,8 and mediator of chemokine activities of RELMα/Hresistin in myeloid cells.1,8 We also reported that, Hresistin/RELMα initiates the inflammatory response to injury at PH onset, through activating damage-associated molecular pattern (DAMP) pathway high-mobility group box-1 (HMGB1).1,4,9 However, it is unclear how Hresistin/RELMα’s diverse inflammatory effects are integrated or how they amplify and sustain inflammation to induce vascular remodeling over time. The NLRP3 inflammasome was recently suggested to be central to the vascular inflammation in PH.10 It mediates the innate response to injury and is associated with the transition to adaptive immunity. Here, we intend to demonstrate the novel concept that Hresistin/RELMα is a critical regulator of the priming and activation stages of the NLRP3 inflammasome. Our preliminary data suggests the hypothesis that Hresistin/RELM ritical α is c to both NLRP3 priming (via HMGB1)11 and NLRP3 activation (via BTK) and production of IL-1β and IL-18 (via critical BTK12 phosphorylation of four specific NLRP3 tyrosine residues) in both macrophages and B cells, leading to pulmonary vascular remodeling and PH. It suggests a major and novel role for Hresistin/RELMα in engaging the NLRP3 inflammasome in the innate immune response to injury and to a sustaining adaptive immune response in the long-term remodeling associated with PH. We address this hypothesis in two aims: Aim 1: To dissect and prove the detailed mechanism of how Hresistin regulates NLRP3 inflammasome in inflammatory cells; Aim 2: To investigate the contribution of Hresistin- regulated inflammasome to vascular remodeling and PH.
项目摘要 大量的研究表明,人类的抗病毒蛋白(Havyn)及其啮齿动物相关的抵抗素样分子(RELM)- α在肺动脉高压(PH)炎症机制中的作用肺中的汉龙水平升高 特发性PAH和硬皮病PH患者1,2与PH的疾病严重程度相关,并可预测死亡率。3 啮齿动物PH模型显示RELMα对肺血管和右心的PH重塑至关重要。3 -7我们 报道了布鲁顿酪氨酸激酶(BTK)作为RELMα/Hkn,8的结合伴侣和趋化因子的介导剂 RELMα/Hlgn在骨髓细胞中的活性。1,8我们还报道,Hlgn/RELMα启动了 PH发作时通过激活损伤相关分子模式(DAMP)对损伤的炎症反应 通路高迁移率族蛋白1(HMGB 1)。1,4,9然而,目前还不清楚HMGB 1/RELMα的多样性 炎症效应是整合的,或者它们如何放大和维持炎症以诱导血管重塑 随着时间 NLRP 3炎性小体最近被认为是PH中血管炎症的中心。 对损伤的先天反应,并与向适应性免疫的转变有关。在此,我们打算 证明了新的概念,即Hynn/RELMα是启动和激活阶段的关键调节因子 NLRP 3炎性小体我们的初步数据表明,假设Hynn/RELM临界 a是c 与NLRP 3引发(通过HMGB 1)11和NLRP 3活化(通过BTK)以及IL-1β和IL-18的产生有关 (via四个特定NLRP 3酪氨酸残基的关键BTK 12磷酸化), 这表明,HALORN/RELMα在肺血管重构和PH中发挥着重要而新颖的作用, 使NLRP 3炎性体参与对损伤的先天免疫应答和对持续适应性免疫应答。 与PH相关的长期重塑中的免疫应答。 我们提出这一假说有两个目的:目的1:剖析和证明Hynn如何在 调节炎性细胞中的NLRP 3炎性体;目的2:研究Hlgn-3在炎症细胞中的作用。 调节炎性小体对血管重构和PH的影响。

项目成果

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Roger A Johns其他文献

Increased Pulmonary Blood Flow as a Regulator of Pulmonary Vascular Remodeling: Role of eNOS ♦ 105
  • DOI:
    10.1203/00006450-199704001-00126
  • 发表时间:
    1997-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Allen D Everett;Timothy D Le Cras;Chun Xue;Roger A Johns
  • 通讯作者:
    Roger A Johns

Roger A Johns的其他文献

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{{ truncateString('Roger A Johns', 18)}}的其他基金

DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension
DAMP 信号介导 HIMF 诱导的肺动脉高压
  • 批准号:
    9976575
  • 财政年份:
    2018
  • 资助金额:
    $ 70.15万
  • 项目类别:
DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension
DAMP 信号介导 HIMF 诱导的肺动脉高压
  • 批准号:
    10206240
  • 财政年份:
    2018
  • 资助金额:
    $ 70.15万
  • 项目类别:
Mechanistic Actions of PDZ Domain Mediated Protein Interactions on Neural Development and Anesthetic-Mediated Neurotoxicity
PDZ 结构域介导的蛋白质相互作用对神经发育和麻醉介导的神经毒性的机制作用
  • 批准号:
    10390873
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Targeting resitin and RELM-beta to treat pulmonary hypertension
靶向抵抗素和 RELM-β 治疗肺动脉高压
  • 批准号:
    8757198
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Targeting PDZ to unravel early anesthetic exposure-produced cognitive dysfunction
靶向 PDZ 来解决早期麻醉暴露引起的认知功能障碍
  • 批准号:
    9016565
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Targeting resitin and RELM-beta to treat pulmonary hypertension
靶向抵抗素和 RELM-β 治疗肺动脉高压
  • 批准号:
    9335421
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Mechanistic Actions of PDZ Domain Mediated Protein Interactions on Neural Development and Anesthetic-Mediated Neurotoxicity
PDZ 结构域介导的蛋白质相互作用对神经发育和麻醉介导的神经毒性的机制作用
  • 批准号:
    10649603
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Mechanistic Actions of PDZ Domain Mediated Protein Interactions on Neural Development and Anesthetic-Mediated Neurotoxicity
PDZ 结构域介导的蛋白质相互作用对神经发育和麻醉介导的神经毒性的机制作用
  • 批准号:
    10212402
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Targeting PDZ to unravel early anesthetic exposure-produced cognitive dysfunction
靶向 PDZ 来解决早期麻醉暴露引起的认知功能障碍
  • 批准号:
    8673354
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
Targeting resitin and RELM-beta to treat pulmonary hypertension
靶向抵抗素和 RELM-β 治疗肺动脉高压
  • 批准号:
    8931049
  • 财政年份:
    2014
  • 资助金额:
    $ 70.15万
  • 项目类别:
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