The study of Eicosanoids as Novel Inflammatory Mediators of CVD in Men and Women with HIV

类花生酸作为男性和女性 HIV 感染者 CVD 新型炎症介质的研究

• 批准号: 10619986
• 负责人: Claudia Martinez
• 金额: $ 71.93万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619986
• 关键词: Address; Affect; Age; Anti-Inflammatory Agents; Attenuated; Automobile Driving; Bioinformatics; Biological; Biological Markers; Biology; Blood Vessels; CD4 Lymphocyte Count; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic; Clinical; Complex; Data; Development; Drug Targeting; Dyslipidemias; Eicosanoid Production; Eicosanoids; Etiology; Event; Exposure to; Female; Fever; Future; Gene Expression; General Population; Genomics; HIV; HIV Infections; Heart Diseases; Immune response; Immune system; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Link; Lipids; Machine Learning; Mass Spectrum Analysis; Measures; Mendelian randomization; Multiomic Data; Non-Steroidal Anti-Inflammatory Agents; Pain; Participant; Pathogenesis; Pathway interactions; Persons; Pharmacology; Plasma; Polyunsaturated Fatty Acids; Process; Proteomics; Regimen; Reporting; Risk Factors; Role; Sex Differences; System; Therapeutic; Thrombosis; Time; Vascular Diseases; Viral; Viral Load result; Virus Diseases; Woman; adjudication; antiretroviral therapy; cardiovascular disorder risk; cardiovascular risk factor; cell regeneration; clinical predictors; clinically relevant; cohort; fatty acid metabolism; genetic predictors; genetic variant; genomic data; genomic locus; illness length; immune activation; immunoregulation; improved; inflammatory marker; insight; lipidomics; men; metabolomics; microbial; multidisciplinary; multiple omics; novel; risk prediction; sex; sexual dimorphism; stroke risk; targeted treatment; therapeutic target; virus identification

Advances in antiretroviral therapies (ART) have greatly improved the survival of people with human immunodeficiency virus (HIV) infection (PWH); yet, the leading cause of death in PWH across all ages is now cardiovascular disease (CVD). While the pathogenesis of HIV-associated CVD is thought to be multifactorial resulting from the interplay of traditional CVD risk factors, exposure to ART, chronic inflammation, and immune activation that persists despite viral suppression; a comprehensive mechanistic framework is lacking to provide further insights into the etiology of CVD in PWH. Importantly, the “female advantage” for CVD risk is attenuated in the context of HIV, with an increase in MI and stroke risk reported in women when compared to men. Inflammation is recognized as a central driving factor in CVD pathogenesis irrespective of HIV status but is more pronounced in PWH. In a study of ART-suppressed PWH within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, our team identified distinct biomarkers of inflammation that predicted inflammatory related clinical events in a sex-specific manner. However, efficient therapies targeting inflammatory processes are still lacking. Accumulating evidence suggests that the upstream initiation of inflammatory activity is governed by products of polyunsaturated fatty acids (PUFAs) and that eicosanoids, the best-characterized bioactive PUFA derivatives, play a role in CVD pathogenesis by modulating vascular tone, cellular regeneration and thrombosis. The COX pathway involved in eicosanoid production is of particular clinical relevance as it is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), used to treat pain, fever and inflammation. Recent advances in mass spectrometry have allowed our team to quantify hundreds of eicosanoids in the plasma of two non-HIV cohorts and detect specific pathways linked to CVD risk, some in a sex-specific manner. However, the causal role of plasma eicosanoids in CVD pathogenesis in PWH has not been elucidated. Therefore, our objective is to leverage CNICS cohort with adjudicated clinial events to elucidate the role of eicosanoids in CVD risk in PWH. We hypothesize that eicosanoids serve as inflammatory mediators of HIV-associated CVD pathogenesis and explain, at least in part, the sexual dimorphism seen in CVD risk. We propose to 1. Characterize plasma eicosanoid profiles of PWH compared to matched non-HIV controls and establish their relationship with CVD risk factors, HIV related factors (disease duration, viral load, CD4 counts), sex and clinical events among 3,000 PWH; 2. Assess causal inference of eicosanoids on cardiovascular events and identify unique genetic loci associated with eicosanoid profiles in PWH, and 3. Integrate lipidomics, metabolomics, proteomics and genomics data with clinical information to detect novel biological pathways and key drivers of cardiovascular risk in PWH and identify novel or repurposed intervention drug targets. The proposed studies will guide future development of efficacious, potentially sex-stratified, interventions for CVD in individuals with and without HIV.

抗逆转录病毒疗法（ART）的进展大大改善了人类感染者的生存率。 免疫缺陷病毒（HIV）感染（PWH）;然而，现在所有年龄段PWH的主要死亡原因是 心血管疾病（CVD）。虽然HIV相关CVD的发病机制被认为是多因素的， 由于传统的CVD危险因素、ART暴露、慢性炎症和免疫系统的相互作用， 尽管病毒受到抑制，但激活仍持续存在;缺乏全面的机制框架来提供 进一步了解PWH中心血管疾病的病因。重要的是，CVD风险的“女性优势”减弱 在艾滋病毒的背景下，与男性相比，女性报告的MI和中风风险增加。 炎症被认为是CVD发病机制中的中心驱动因素，而与HIV状态无关， 在PWH中更为明显。在一项在综合临床研究的CFAR网络内进行的ART抑制PWH研究中， 系统（CNICS）队列，我们的团队确定了不同的炎症生物标志物，预测炎症 以性别特异性方式与临床事件相关。然而，针对炎症过程的有效疗法 仍然缺乏。越来越多的证据表明，炎症活动的上游启动是 由多不饱和脂肪酸（PUFAs）的产物控制，而类花生酸，最具特征的 生物活性PUFA衍生物，通过调节血管张力、细胞张力和细胞凋亡在CVD发病中起作用。 再生和血栓形成。参与类花生酸产生的考克斯途径具有特殊的临床意义 相关性，因为它是非甾体抗炎药（NSAID）的主要靶点，用于治疗疼痛、发热 和炎症。质谱分析的最新进展使我们的团队能够量化数百种 在两个非HIV队列的血浆中检测类花生酸，并检测与CVD风险相关的特定途径，其中一些在 性的方式。然而，血浆类花生酸在PWH中CVD发病机制中的因果作用尚未得到证实。 被阐明。因此，我们的目标是利用具有裁定临床事件的CNICS队列， 阐明类花生酸在PWH CVD风险中的作用。我们假设类二十烷酸作为炎症因子 HIV相关的CVD发病机制的介质，并解释，至少部分地， CVD风险。我们建议1。与匹配的非HIV相比，表征PWH的血浆类花生酸谱 控制并建立其与CVD风险因素，HIV相关因素（疾病持续时间，病毒载量， CD 4计数）、性别和临床事件; 2.评估类二十烷酸对 心血管事件和鉴定与PWH中类花生酸谱相关的独特遗传基因座，和3. 将脂质组学、代谢组学、蛋白质组学和基因组学数据与临床信息相结合， PWH心血管风险的生物学途径和关键驱动因素，并确定新的或重新设计的干预措施 药物靶点拟议的研究将指导未来开发有效的，潜在的性别分层， 在有和没有艾滋病毒的个体中进行CVD干预。