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

• 批准号: 10443548
• 负责人: Susan Cheng
• 金额: $ 80.87万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10443548
• 关键词: Acids; Adverse event; Analytical Chemistry; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Atherosclerosis Risk in Communities; Biological Assay; Biological Factors; Biological Markers; Biological Process; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cessation of life; Chronic; Clinical; Cohort Studies; Communities; Complex; Conflict (Psychology); Development; Disease; EFRAC; Eicosanoids; Eicosapentaenoic Acid; Epidemiology; Equilibrium; Exhibits; Experimental Models; Exposure to; Family; Follow-Up Studies; Framingham Heart Study; Goals; Heart Diseases; Heart failure; Hospitalization; Human; Hypertension; Image; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Leukotrienes; Linoleic Acids; Lipids; Lipoxins; Longitudinal Studies; Mass Spectrum Analysis; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Morbidity - disease rate; Mus; Myocardial dysfunction; Natriuresis; Obesity; Outcome; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Physiological; Plasma; Play; Polyunsaturated Fatty Acids; Prognosis; Prostaglandins; Risk; Risk Factors; Role; Sample Size; Serum; Signal Transduction; Source; Stress; Symptoms; TNF gene; Time; Tissues; Variant; Woman; Work; adverse outcome; antagonist; base; cardiogenesis; clinical risk; cohort; constriction; experimental study; fatty acid metabolism; gamma-Linolenic Acid; hemodynamics; improved; inflammatory marker; insight; ischemic injury; lipid mediator; longitudinal animal study; men; mortality; mouse model; novel; preservation; pressure; prospective; stressor; systemic inflammatory response; therapeutic target; therapeutically effective; trait; ventricular hypertrophy

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 慢性炎症的定义是局部和全身促炎因子的持续升高， 与社区心力衰竭的发展和进展有关。尽管如此，有证据表明 对于作为关键的特定炎症途径的可能性，在人类中的研究很少且相互矛盾 疾病的机械性驱动力，进而成为潜在的高产量治疗靶点。这个问题已经 在一定程度上，这是由于之前主要关注下游而不是上游的炎症介质。 越来越多的证据表明，炎症的上游介质更有可能起到因果作用 在疾病的发病机制，因此，作为有效的治疗靶点。上游的启动 人类的炎症主要是由多不饱和脂肪酸的小分子脂分子效应分子控制的 新陈代谢，称为二十烷类化合物。这些生物活性脂质既有促炎活性，又有抗炎活性。 包括前列腺素、脂蛋白和白三烯。到目前为止，二十烷类化合物通路之间的相互作用 心力衰竭的特征和结果仍然知之甚少。因此，我们建议提供一个更多的 详细了解上游二十烷类通路如何可变地活跃、不平衡和 对个人发展为心力衰竭的倾向感到不安。高级质谱学 现在的方法允许快速和准确地定量多达数百个上游二十烷类化合物 代表多种酶来源的介体。我们将利用这些方法来综合分析 不同的促炎和抗炎二十烷类化合物，并检查它们与心力衰竭危险因素和 对居住在社区的男性和女性进行的纵向研究的结果。同时，我们将分析 二十烷类化合物在一项即将到来的心力衰竭动物模型的纵向研究中。我们的具体目标是：(一) 评估循环二十烷基类炎症介质是否与心力衰竭危险因素相关 和社区发病率；(2)循环二十烷类化合物与不良后果之间的关系 已建立的心力衰竭；以及，(3)研究二十烷类化合物的时间和组织特异性相关性 心力衰竭实验模型的变异。我们全面调查的系统方法 上游炎症活动的成分与心力衰竭结局的关系 Risk有望为临床上重要的心功能障碍的决定因素提供重要的见解。vt.给出 它的重点是上游的炎症活动，这项工作将为后续研究调查 抗炎疗法(现有的和新的药物)对调节不同疾病的变化的疗效 二十烷类化合物以及结果。