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Metabolic Regulation of Inflammatory Immune Responses in Cardiovascular Disease

Metabolic Regulation of Inflammatory Immune Responses in Cardiovascular Disease
心血管疾病炎症免疫反应的代谢调节
批准号:
9978626
负责人:
Cornelia M. Weyand
金额:
$66.82万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-01 至 2022-07-31

项目摘要

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中文摘要
翻译
先天性和适应性免疫系统的异常是心血管疾病的关键致病因素, 这些疾病包括高血压、动脉粥样硬化和心肌病。目前的建议侧重于 巨噬细胞,其通过多种效应器功能,例如促炎性细胞因子, 炎性细胞因子释放、脂质和碎片的无效去除、基质降解和抗原 呈递给T淋巴细胞。在初步研究中,我们已经表明, 冠状动脉疾病或高血压具有高炎症表型并产生过量的IL-1 β, IL-6。患者源性巨噬细胞中的细胞因子过度产生可通过限制葡萄糖或 清除活性氧(ROS)。我们已经确定了潜在的分子机制, 丙酮酸激酶M2(PKM 2)是一种氧化还原敏感性分子,其作为四聚体起作用, 细胞质代谢物激酶和作为二聚体作为促炎性核蛋白激酶。在 在患有动脉粥样硬化或高血压疾病的患者中,PKM 2主要二聚化并输入到血管中。 核,一种异常,连接改变代谢调节与过度炎症免疫。在 本质上,在心血管疾病患者中,葡萄糖过度利用会刺激炎症巨噬细胞 通过ROS诱导的PKM 2核转位发挥作用,其中该酶促进细胞因子 糖酵解的产生和前馈激活;类似于癌细胞的瓦尔堡效应的病理学。 与项目1和3密切合作,项目2将定义耦合的基本分子机制, 血管炎症中的代谢和功能异常。旨在发现可采取行动的 炎症免疫反应的诊断和治疗靶点,我们将重点关注葡萄糖-ROS- PKM 2通路。具体目标1将寻求机械地了解如何ROS生产和糖酵解 通量决定PKM 2的寡聚状态、细胞定位和功能。具体目标2致力于 冠状动脉疾病和高血压患者巨噬细胞代谢和功能的比较分析 来剖析共同的和选择性的病理。为了了解患者源性巨噬细胞是如何 代谢重编程,这一目标将利用一种新的表观遗传技术(ATAC seq),以确定平衡 基因和先驱转录因子。在具体目标3中,我们将揭示PKM 2在调节细胞凋亡中的作用。 致病性巨噬细胞功能谱,并确定葡萄糖成瘾对T细胞的影响 免疫(Th 1、Th 17、Treg和Thf免疫应答)。具体目标4将探讨分子 炎性巨噬细胞和癌细胞之间的共性可以用于新的治疗, 心血管疾病在临床前研究中,我们将测试开发的小分子抑制剂是否能治疗 癌细胞中的瓦尔堡效应可以被重新用于抑制心血管疾病中的炎症。
英文摘要
Abnormalities in the innate and adaptive immune system are key pathogenic factors in cardiovascular disease, including hypertension, atherosclerosis and cardiomyopathy. The current proposal focusses on macrophages, which contribute to inflammatory damage through multiple effector functions, e.g. pro- inflammatory cytokine release, inefficient removal of lipids and debris, matrix degradation and antigen presentation to T lymphocytes. In preliminary studies we have shown that macrophages from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce excess IL-1 and IL-6. Cytokine overproduction in patient-derived macrophages is correctable by restricting glucose or scavenging reactive oxygen species (ROS). We have pinpointed the underlying molecular mechanism to the enzyme pyruvate kinase M2 (PKM2), a redox-sensitive molecule, which as a tetramer functions as a cytoplasmic metabolite kinase and as a dimer acts as an inflammation-promoting nuclear protein kinase. In patients with atherosclerotic or hypertensive disease, PKM2 is primarily dimerized and imported into the nucleus, an abnormality that connects altered metabolic regulation with excess inflammatory immunity. In essence, in patients with cardiovascular disease, glucose overutilization fuels inflammatory macrophage functions through ROS-induced nuclear translocation of PKM2, where the enzyme promotes cytokine production and feed-forward activation of glycolysis; a pathology resembling the Warburg effect of cancer cells. Working closely with Project 1 and 3, Project 2 will define basic molecular mechanisms that couple metabolic and functional abnormalities in vascular inflammation. Aiming for the discovery of actionable diagnostic and therapeutic targets in inflammatory immune responses, we will focus on the glucose-ROS- PKM2 pathway. Specific Aim 1 will seek to mechanistically understand how ROS production and glycolytic flux determine the oligomeric state, cellular localization and function of PKM2. Specific Aim 2 is devoted to a comparative metabolic and functional analysis of macrophages in coronary artery disease and in hypertension to dissect shared and selective pathologies. In an effort to understand how patient-derived macrophages are metabolically reprogrammed, this aim will utilize a novel epigenetic technique (ATAC seq) to identify poised genes and pioneer transcription factors. In Specific Aim 3, we will reveal the role of PKM2 in regulating the spectrum of pathogenic macrophage functions and determine the impact of glucose addiction on T cell immunity (Th1, Th17, Treg and Thf immune responses). Specific Aim 4 will explore whether molecular commonalities between inflammatory macrophages and cancer cells can be exploited for novel therapies in cardiovascular disease. In preclinical studies we will test whether small molecule inhibitors developed to treat the Warburg effect in cancer cells can be repurposed to suppress inflammation in cardiovascular disease.
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T Cell Immunity in Giant Cell Arteritis
  • 批准号:
    10457645
  • 项目类别:
  • 资助金额:
    $35.48万
  • 财政年份:
    2018
  • 负责人:
    Cornelia M. Weyand
  • 依托单位:
T Cell Immunity in Giant Cell Arteritis
  • 批准号:
    9523030
  • 项目类别:
  • 资助金额:
    $39.25万
  • 财政年份:
    2018
  • 负责人:
    Cornelia M. Weyand
  • 依托单位:
The NOTCH Signaling Pathway in Large Vessel Vasculitis
  • 批准号:
    10316892
  • 项目类别:
  • 资助金额:
    $56.91万
  • 财政年份:
    2014
  • 负责人:
    Cornelia M. Weyand
  • 依托单位:
The NOTCH Signaling Pathway in Large Vessel Vasculitis
  • 批准号:
    8629407
  • 项目类别:
  • 资助金额:
    $41.57万
  • 财政年份:
    2014
  • 负责人:
    Cornelia M. Weyand
  • 依托单位:
海外基金