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.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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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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