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：
Susan Cheng
金额：
$ 80.87万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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

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

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明显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。