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：
10558470
负责人：
Christy Leigh Avery
金额：
$ 91.78万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10558470
关键词：
Address Adult Affect Attenuated Biochemical Biological Assay Blood Pressure C-reactive protein Cardiometabolic Disease Cardiovascular Diseases Chronic Data Development Disease Disparity Eicosanoid Modulation Eicosanoids Eicosatrienoic Acid Ethnic Population Fatty Acids Foundations Framingham Heart Study Future Genotype Hispanic Hispanic Community Health Study/Study of Latinos Human Incidence Inflammation Inflammation Mediators Inflammatory Insulin Resistance Investigation Latino Population Link Linolenic Acids Lipids Lipoxins Mass Spectrum Analysis Measures Mediating Mediator Mendelian randomization Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Obesity Participant Pathogenesis Pathologic Pathway interactions Phenotype Plasma Population Prevention Prostaglandins Public Health Regulation Research Resources Risk Risk Factors Role Shoulder Source Statistical Methods Structure Techniques Technology Testing Therapeutic Intervention Time Work burden of illness cardiometabolic risk cardiometabolism case control cohort cost effective design ethnic disparity ethnic minority follow-up genome wide association study genomic data health disparity high risk inflammatory marker inflammatory modulation insight lipid mediator mortality multi-ethnic novel novel therapeutics population based prevent prospective racial disparity racial minority racial population small molecule systemic inflammatory response 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) 导致发病率和死亡率显着增加且不断增加负担对少数种族/族裔影响尤为严重，包括西班牙裔/拉丁裔 (H/L)。人口负担、既定的差异以及逆转进展或预防长期 T2D 治疗的可用性有限术语并发症强调迫切需要澄清可能作为新目标的机制途径用于预防和治疗。慢性低度炎症是一种广泛认可的常见病理学与其他种族/族裔相比，心脏代谢危险因素和 T2D 的特征，尤其是 H/L 人群团体；识别慢性低度炎症的特定介质可以极大地加强定制化的努力现有药物或开发新疗法，尤其是在风险最高的人群中。先前尝试检查慢性低度炎症的特定介质因关注下游标记物而受到限制，包括 C 反应蛋白，它们不太可能是因果关系或难以可靠测量。上游全身炎症的调节又由脂肪酸衍生的脂质介质（称为类二十烷酸）介导。尽管某些类二十烷酸与心脏代谢危险因素和 T2D 相关，但先前的研究表明仅评估了人类中少数最丰富的类二十烷酸。我们建议解决这个重大问题通过利用分析质谱 (MS) 的进步，现在可以快速、准确地对跨越主要生物合成途径的 >150 种类二十烷酸进行准确定量。将检测类二十烷酸在基于深度表型人群的西班牙裔社区健康研究/拉丁裔研究 (SOL) 队列中，能够在已确定心脏代谢风险的 H/L 人群中对研究假设进行经济高效的测试因素和 T2D 差异。具体来说，我们将识别与相关的已知和新型类二十烷酸心脏代谢危险因素和 T2D，并利用现有基因组学数据进行因果推断研究和评估关键类二十烷酸的机制框架。这项工作将深入了解 H/L 中心脏代谢疾病的潜在机制，确定健康差异的潜在来源基因混合队列，并为未来的炎症调节研究提供重要基础旨在减轻广大人群心脏代谢疾病负担的疗法。