Inflammatory mediators of cardiometabolic risk in Latinos

拉丁裔心脏代谢风险的炎症介质

基本信息

批准号：
9909255
负责人：
Christy Leigh Avery
金额：
$ 97.95万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909255
关键词：
Address Adult Affect Attenuated Biochemical Biological Assay Blood Pressure C-reactive protein Cardiovascular Diseases Chronic Data Development Disease Eicosanoids Eicosatrienoic Acid Ethnic group Fatty Acids Foundations Framingham Heart Study Future Genotype Hispanic Community Health Study/Study of Latinos Hispanics Human Incidence Inflammation Inflammation Mediators Inflammatory Insulin Resistance Investigation Latino Link Linolenic Acids Lipids Lipoxins Mass Spectrum Analysis Measures Mediating Mediator of activation protein Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Obesity Participant Pathogenesis Pathologic Pathway interactions Phenotype Plasma Population Prevention Prostaglandins Prothrombin Public Health Randomized Regulation Research Resources Risk Risk Factors Role Shoulder Source Statistical Methods Structure Study of Latinos Techniques Testing Therapeutic Intervention Time Work burden of illness cardiometabolic risk cardiometabolism case control cohort cost effective design ethnic minority population follow-up genome wide association study genomic data health disparity high risk inflammatory marker insight lipid mediator mortality novel novel therapeutics population based prevent prospective racial and ethnic racial and ethnic disparities small molecule targeted treatment therapeutic candidate therapeutic target

项目摘要

ABSTRACT Cardiometabolic risk factors and type 2 diabetes (T2D) impart a substantial and growing morbidity and mortality burden that disproportionally affects racial/ethnic minorities, including Hispanic/Latinos (H/L). The population burden, established disparities, and limited availability of T2D treatments to reverse progression or prevent long- term complications underscore an urgent need to clarify mechanistic pathways that may serve as novel targets for prevention and treatment. Chronic low-grade inflammation is a widely recognized common pathological feature underling cardiometabolic risk factors and T2D, particularly in H/L when compared to other racial/ethnic groups; identifying specific mediators of chronic low-grade inflammation could greatly enhance efforts to tailor existing agents or develop of novel therapies, especially in populations at highest risk. Prior attempts to examine specific mediators of chronic low-grade inflammation have been limited by a focus on downstream markers, including C-reactive protein, which are less likely to be causal or are difficult to reliably measure. Upstream regulation of systemic inflammation is in turn mediated by fatty acid derived lipid mediators termed eicosanoids. Although select eicosanoids have been associated with cardiometabolic risk factors and T2D, prior studies have only assessed a handful of the most abundant eicosanoids in humans. We propose to address this major research gap by leveraging advances in analytical mass spectrometry (MS) that now enable the rapid and accurate quantification of >150 eicosanoids spanning major biosynthetic pathways. Eicosanoids will be assayed in the deeply-phenotyped population-based Hispanic Community Health Study/Study of Latinos (SOL) cohort, enabling cost-effective testing of study hypotheses in a H/L population with established cardiometabolic risk factor and T2D disparities. Specifically, we will identify known and novel eicosanoids associated with cardiometabolic risk factors and T2D, as well as leverage existing genomics data to conduct causal inference studies and evaluate mechanistic frameworks for key eicosanoids. This work will shed insight into the mechanisms underlying cardiometabolic disease in H/L, identify potential sources of health disparities in a genetically admixed cohort, and provide an essential foundation for future studies of inflammatory-modulating therapies aimed at reducing the burden of cardiometabolic disease in the population at large.

抽象的心脏代谢危险因素和2型糖尿病（T2D）赋予了巨大的发病率和死亡率对种族/族裔少数民族的负担，包括西班牙裔/拉丁裔（H/L）。人口负担，确定差异以及T2D处理的有限可用性，以逆转或预防长期术语并发症强调了迫切需要澄清可能用作新目标的机械途径用于预防和治疗。慢性低度炎症是一种公认的常见病理与其他种族/种族相比群体；确定慢性低级炎症的特定介体可以大大加强量身定制的努力现有的药物或开发新疗法，尤其是在风险最高的人群中。事先尝试检查慢性低度炎症的特定介体受到关注下游标记的限制，包括C反应性蛋白质，不太可能是因果关系或难以可靠地测量的。上游全身性炎症的调节反过来又由称为类类酸的脂肪酸衍生的脂质介质介导。尽管精选的类类与心脏代谢危险因素和T2D有关，但先前的研究具有仅评估了人类中少数最丰富的类花生酸酯。我们建议解决这个专业通过利用分析质谱法（MS）的进步来研究差距跨越主要生物合成途径的> 150个类固醇的精确定量。 eicosanoids将被分析在基于人群的深层型西班牙裔社区健康研究/拉丁裔（SOL）同类研究中在患有既定心脏代谢风险的H/L人群中对研究假设进行成本效益的检验因素和T2D差异。具体而言，我们将确定与心脏代谢危险因素和T2D，以及利用现有的基因组数据进行因果推断研究和评估关键类固醇的机理框架。这项工作将洞悉 H/L中心脏代谢疾病的基础机制，确定A中的健康差异的潜在来源遗传上混合的队列，为将来的炎症调节研究提供了重要的基础旨在减轻整个人群中心脏代谢疾病的负担。