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)的进展极大地提高了人类感染者的存活率 免疫缺陷病毒(HIV)感染(PWH)；然而，所有年龄段PWH的主要死亡原因是 心血管疾病(CVD)。而HIV相关心血管疾病的发病机制被认为是多因素的 由传统的心血管疾病危险因素、暴露于抗逆转录病毒药物、慢性炎症和免疫的相互作用所致 尽管病毒受到抑制，激活仍然存在；缺乏一个全面的机制框架来提供 对PWH中心血管疾病病因的进一步认识。重要的是，女性对心血管疾病风险的优势被削弱了。 在艾滋病毒方面，与男性相比，报告的女性心肌梗塞和中风风险增加。 炎症被认为是心血管疾病发病的中心驱动因素，与艾滋病毒状态无关，但 在PWH中更为明显。在综合临床CFAR网络中ART抑制PWH的研究 系统(CNICs)队列，我们的团队确定了预测炎症的不同炎症生物标志物 以特定性别的方式发生相关的临床事件。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)和二十烷类化合物的产物控制，特征最好 生物活性多不饱和脂肪酸衍生物，通过调节血管张力，细胞 再生和血栓形成。环氧合酶途径参与二十烷类化合物的产生具有特殊的临床意义。 因为它是用于治疗疼痛、发烧的非类固醇抗炎药(NSAIDs)的主要靶点 和炎症。质谱学的最新进展使我们的团队能够量化数百种 在两个非HIV人群的血浆中发现二十烷类化合物，并检测与心血管疾病风险相关的特定途径，其中一些是在 特定性别的方式。然而，血浆二十烷基类化合物在PWH的CVD发病机制中的因果作用尚未见报道。 已被阐明。因此，我们的目标是利用CNICs队列和已裁决的临床事件来 阐明二十烷类化合物在PWH心血管疾病风险中的作用。我们假设二十烷类化合物是炎症性的 HIV相关心血管疾病发病机制的介体，并至少部分解释了在 心血管疾病风险。我们建议1.与匹配的非HIV患者相比，PWH患者的血浆二十烷基类化合物的特征 控制并建立它们与心血管疾病危险因素、艾滋病毒相关因素(病程、病毒载量、 3,000名PWH患者中的性行为和临床事件；2.评估二十烷类化合物对 心血管事件，并确定与PWH中二十烷类物质特征相关的独特遗传基因座，以及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，以检测新的 PWH心血管风险的生物学途径和关键驱动因素，并确定新的或重新定位的干预措施 毒品目标。拟议的研究将指导未来有效的，潜在的性别分层， 艾滋病毒携带者和非艾滋病毒携带者心血管疾病的干预。