Resolution of Inflammation in Heart Failure Post-Myocardial Infarction

心肌梗塞后心力衰竭炎症的消退

基本信息

  • 批准号:
    9155912
  • 负责人:
  • 金额:
    $ 36.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-01 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

Heart failure (HF) after myocardial infarction (MI) is a significant cause of morbidity and mortality. Identifying the events that limit adverse remodeling of the left ventricle (LV) post-MI will provide therapeutic targets to prevent, slow, or reverse progression to HF. MI initiates the “get-in” signal for immune cells including neutrophils, which if unchecked causes uncontrolled pro-inflammatory activity that in turn leads to HF. Our post-MI studies suggest that spleen coordinates the resolution of inflammation through a cardiosplenic pathway. These findings reveal an urgent clinical need to establish the mechanisms by which the spleen mediates this resolution. It was previously believed that resolution of inflammation is an inert process, but emerging data confirms that this is an active process managed by specialized pro-resolving molecules (SPMs) derived from omega-3 and omega-6 fatty acids. Our R00 study in an HF setting confirms that the spleen produces various SPMs, including lipoxins, resolvins, and maresins post-MI, and exogenous treatment with resolvin D1 (RvD1) clears inflammation in a cardiosplenic manner. We discovered that exogenous RvD1 clears neutrophils and resolves inflammation by activating neutrophil-expressed formyl peptide receptor 2 (FPR2) in the left ventricle and spleen post-MI. This proof-of-concept study using RvD1 in mice provides the foundation for investigation of the resolvins-mediated mechanism of action in chronic HF. These data implicate activation of neutrophil receptors in promoting the “get-out” signal for effective resolution of inflammation post-MI. To achieve our overall goal of activating immune cells in the healing phase after MI, we propose to establish: 1) the role of RvD1 in resolution of inflammation in chronic HF; 2) whether activation of this “get-out” signal is enough to resolve post-MI inflammation in HF using FPR2 knockout mice to abolish RvD1 action and resultant HF; and 3) the novel mechanism of action of RvD1 on neutrophil-expressed CD10 in the cardiosplenic axis, as suggested by our innovative in silico computational modeling. Our initial studies in mice have confirmed the role of RvD1 in acute HF. Now, we propose a mechanistic study to extend in silico, ex vivo, and acute HF (day 5) outcomes to chronic HF (day 28), which is key for translation and to indicate survival benefit to HF patients. Non-immunosuppressive pro-resolving therapy is an unmet medical need and has the potential to be the first ever effective therapy to control chronic inflammation and delay HF in a cardiosplenic manner. These studies will identify immune cell-specific novel targets for lipid mediators in a ligand-receptor-specific pathway, rather than antibody or cytokine-specific inhibition, which will likely enhance therapeutic applications in patients with HF within the next 5-6 years.
心肌梗死(MI)后心力衰竭(HF)是发病率和死亡率的重要原因。识别 限制MI后左心室(LV)不良重塑的事件将提供治疗靶点, 预防、减缓或逆转HF的进展。MI启动免疫细胞的“进入”信号,包括 中性粒细胞,如果不加抑制,会导致不受控制的促炎活性,进而导致HF。我们 心肌梗死后的研究表明,脾脏通过心脾协调炎症的消退, 通路这些发现揭示了迫切的临床需要,以建立机制,脾 调解这一决议。以前认为炎症的消退是一个惰性过程,但 新出现的数据证实,这是一个由专门的前解析分子(SPM)管理的主动过程 源自欧米茄-3和欧米茄-6脂肪酸。我们在HF环境中的R 00研究证实, 产生各种SPM,包括脂氧素、消退素和MI后maresins,以及用 Resolvin D1(RvD 1)以心脾方式清除炎症。我们发现外源性RvD 1可以清除 中性粒细胞,并通过激活嗜中性粒细胞表达的甲酰肽受体2(FPR 2)来解决炎症。 心肌梗死后的左心室和脾脏这项在小鼠中使用RvD 1的概念验证研究为 用于研究消退素介导的慢性HF作用机制。这些数据表明 中性粒细胞受体在促进“脱身”信号以有效解决MI后炎症中的作用。到 为了实现我们在MI后愈合阶段激活免疫细胞的总体目标,我们建议建立:1) RvD 1在慢性HF炎症消退中的作用; 2)是否激活了这种“离开”信号, 使用FPR 2敲除小鼠消除RvD 1作用并产生足以解决HF中MI后炎症的结果 HF;和3)RvD 1对心脾轴中嗜中性粒细胞表达的CD 10的新作用机制,如 这是由我们创新的计算机模拟提出的。我们对小鼠的初步研究已经证实了 RvD 1在急性HF中的作用现在,我们提出了一个机制研究,以扩大在硅片,离体,和急性HF(天 5)慢性HF(第28天)的结局,这是转换的关键,并表明HF患者的生存获益。 非免疫抑制促消退疗法是一种未满足的医疗需求,有可能成为第一种 以心脾方式控制慢性炎症和延迟HF的有效治疗。这些研究 将在配体-受体特异性途径中识别脂质介质的免疫细胞特异性新靶点, 比抗体或精氨酸特异性抑制,这将可能提高患者的治疗应用 HF在未来5-6年内。

项目成果

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Ganesh V Halade其他文献

Association of Common Foods with Inflammation and Mortality: Analysis from a Large Prospective Cohort Study.
常见食物与炎症和死亡率的关联:大型前瞻性队列研究的分析。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Nicholas W. Carris;Rahul Mhaskar;Emily Coughlin;Easton Bracey;S. Tipparaju;Koushik R Reddy;Hariom Yadav;Ganesh V Halade
  • 通讯作者:
    Ganesh V Halade

Ganesh V Halade的其他文献

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{{ truncateString('Ganesh V Halade', 18)}}的其他基金

Lipoxygenase Signaling in Heart Failure Pathology
心力衰竭病理学中的脂氧合酶信号转导
  • 批准号:
    10085527
  • 财政年份:
    2019
  • 资助金额:
    $ 36.75万
  • 项目类别:
Lipoxygenase Signaling in Heart Failure Pathology
心力衰竭病理学中的脂氧合酶信号转导
  • 批准号:
    10409634
  • 财政年份:
    2019
  • 资助金额:
    $ 36.75万
  • 项目类别:
Lipoxygenase Signaling in Heart Failure Pathology
心力衰竭病理学中的脂氧合酶信号转导
  • 批准号:
    9979948
  • 财政年份:
    2019
  • 资助金额:
    $ 36.75万
  • 项目类别:
Lipoxygenase Signaling in Heart Failure Pathology
心力衰竭病理学中的脂氧合酶信号转导
  • 批准号:
    9813328
  • 财政年份:
    2019
  • 资助金额:
    $ 36.75万
  • 项目类别:
Resolution of Inflammation in Heart Failure Post-Myocardial Infarction
心肌梗塞后心力衰竭炎症的消退
  • 批准号:
    10085520
  • 财政年份:
    2016
  • 资助金额:
    $ 36.75万
  • 项目类别:
DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction
DHA 在肥胖介导的心肌梗死后心脏重塑中的机制
  • 批准号:
    8683380
  • 财政年份:
    2011
  • 资助金额:
    $ 36.75万
  • 项目类别:
DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction
DHA 在肥胖介导的心肌梗死后心脏重塑中的机制
  • 批准号:
    8727214
  • 财政年份:
    2011
  • 资助金额:
    $ 36.75万
  • 项目类别:
DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction
DHA 在肥胖介导的心肌梗死后心脏重塑中的机制
  • 批准号:
    8309090
  • 财政年份:
    2011
  • 资助金额:
    $ 36.75万
  • 项目类别:
DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction
DHA 在肥胖介导的心肌梗死后心脏重塑中的机制
  • 批准号:
    8165292
  • 财政年份:
    2011
  • 资助金额:
    $ 36.75万
  • 项目类别:
DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction
DHA 在肥胖介导的心肌梗死后心脏重塑中的机制
  • 批准号:
    8730082
  • 财政年份:
    2011
  • 资助金额:
    $ 36.75万
  • 项目类别:

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