Mediators of Systemic Inflammation and Heart Failure Risk in the Community

社区中全身炎症和心力衰竭风险的中介因素

基本信息

  • 批准号:
    10443548
  • 负责人:
  • 金额:
    $ 80.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, has been implicated in the development and progression of heart failure in the community. Nonetheless, evidence in humans is scant and conflicting regarding the potential for specific inflammatory pathways to serve as key mechanistic drivers of disease and, in turn, as potentially high-yield therapeutic targets. This problem has arisen, in part, from a predominant prior focus on downstream rather than upstream mediators of inflammation. Accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, thus, serve as effective therapeutic targets. The upstream initiation of inflammation in humans is governed primarily by small lipid molecule effectors of polyunsaturated fatty acid metabolism, termed eicosanoids. These bioactive lipid species exhibit both pro- and anti-inflammatory activity and include prostaglandins, lipoxins, and leukotrienes. To date, the interactions between eicosanoid pathways and heart failure traits and outcomes remain poorly understood. Therefore, we proposed to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual’s propensity for developing heart failure. Advanced mass spectrometry methods now allow for the rapid and accurate quantification of up to hundreds of upstream eicosanoid mediators representing multiple enzymatic origins. We will use these methods to comprehensively assay distinct pro- and anti-inflammatory eicosanoids and examine their relation to heart failure risk factors and outcomes in a longitudinal study of men and women living in the community. In parallel, we will profile eicosanoids in a longitudinal study of an animal model of impending heart failure. Our specific aims are: (1) to assess whether circulating eicosanoid mediators of inflammation are associated with heart failure risk factors and incidence in the community; (2) to relate circulating eicosanoids with adverse outcomes in the setting of established heart failure; and, (3) to investigate the temporal and tissue-specific correlates of eicosanoid variation in an experimental model of heart failure. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in relation to heart failure outcomes across the spectrum of risk promises to yield important insights into the determinants of clinically important cardiac dysfunction. Given its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct eicosanoids as well as outcomes.
项目摘要/摘要 慢性炎症是由局部和全身性促炎性因素持续升高所定义的,具有 在社区心力衰竭的发展和发展中隐含。尽管如此,证据 在人类中,关于特定的炎症途径的潜力很少,而且是矛盾的 疾病的机械驱动因素,反过来是潜在的高收益治疗靶标。这个问题有 在某种程度上,主要是对下游而不是上游炎症介体的主要关注。 积累的证据表明,炎症上游介体更有可能发挥因果作用 在疾病发病机理中,因此充当有效的治疗靶标。上游的开始 人类的炎症由多不饱和脂肪酸的小脂质分子效应支配 代谢,称为eicosanoids。这些生物活性脂质物种表现出促和抗炎活性 包括前列腺素,lipoxins和白细胞。迄今为止,类花生酸途径之间的相互作用 和心力衰竭的特征和结果仍然知之甚少。因此,我们建议提供更多 详细了解上游的类花生酸途径如何可变,不平衡和 与个人发展心力衰竭的承诺有关。晚期质谱法 现在,方法可以快速准确地量化多达数百种上游类eicosanoid 代表多种酶促起源的介体。我们将使用这些方法全面测定 独特的促和抗炎类花生酸酯,并检查其与心力衰竭危险因素的关系和 在一项纵向研究中居住在社区中的男人和女人的结果。并行,我们将概括 在对即将发生心力衰竭的动物模型的纵向研究中,花生酸酯。我们的具体目的是:(1) 评估炎症的循环类花生酸介质是否与心力衰竭危险因素有关 和社区中的事件; (2)将循环类花生酸与不良结果相关联 建立心力衰竭;和(3)研究类花生酸的暂时和组织特异性相关性 心力衰竭实验模型的变化。我们全面研究的系统方法 上游炎症活动的成分与整个频谱的心力衰竭结局有关 风险有望对临床上重要的心脏功能障碍的确定性产生重要的见解。给出 它的重点是上游炎症活动,这项工作将为调查的后续研究铺平道路 抗炎疗法(现有和新型药物)的功效调节不同的变化 类花生酸和结果。

项目成果

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Susan Cheng其他文献

Susan Cheng的其他文献

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{{ truncateString('Susan Cheng', 18)}}的其他基金

Vaccine Induced Immune-Inflammatory Response and Cardiovascular Risk
疫苗诱导的免疫炎症反应和心血管风险
  • 批准号:
    10608977
  • 财政年份:
    2021
  • 资助金额:
    $ 80.87万
  • 项目类别:
Vaccine Induced Immune-Inflammatory Response and Cardiovascular Risk
疫苗诱导的免疫炎症反应和心血管风险
  • 批准号:
    10378764
  • 财政年份:
    2021
  • 资助金额:
    $ 80.87万
  • 项目类别:
MAE-WEST SCORE Project 1 Population
MAE-WEST SCORE 项目 1 人口
  • 批准号:
    10450761
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
CORALE-SeroNet Admin Core
CORALE-SeroNet 管理核心
  • 批准号:
    10222433
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
MAE-WEST SCORE Research Support Core - Bioinformatics Core
MAE-WEST SCORE 研究支持核心 - 生物信息学核心
  • 批准号:
    10198758
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
MAE-WEST SCORE Project 1 Population
MAE-WEST SCORE 项目 1 人口
  • 批准号:
    10198760
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2
SARS-CoV-2 免疫炎症反应的多样性和决定因素
  • 批准号:
    10222432
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
MAE-WEST SCORE Research Support Core - Bioinformatics Core
MAE-WEST SCORE 研究支持核心 - 生物信息学核心
  • 批准号:
    10450758
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
CORALE-SeroNet Admin Core
CORALE-SeroNet 管理核心
  • 批准号:
    10688395
  • 财政年份:
    2020
  • 资助金额:
    $ 80.87万
  • 项目类别:
Ventricular-vascular coupling in the elderly: lifecourse determinants, trajectories and prognostic significance
老年人的心室-血管耦合:生命历程的决定因素、轨迹和预后意义
  • 批准号:
    10202703
  • 财政年份:
    2019
  • 资助金额:
    $ 80.87万
  • 项目类别:

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  • 财政年份:
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