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）的进步极大地提高了人类携带者的生存率 免疫缺陷病毒（HIV）感染（PWH）；然而，现在所有年龄段的感染者死亡的主要原因是 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 传统 CVD 危险因素、ART 暴露、慢性炎症和免疫相互作用的结果 尽管病毒受到抑制，激活仍持续存在；缺乏全面的机制框架来提供 进一步深入了解 PWH 中 CVD 的病因。重要的是，心血管疾病风险的“女性优势”被削弱 在艾滋病毒的背景下，与男性相比，女性发生心肌梗死和中风的风险增加。 炎症被认为是 CVD 发病机制的核心驱动因素，与 HIV 状态无关，但 产后出血中更为明显。在综合临床 CFAR 网络内一项关于 ART 抑制的 PWH 的研究中 Systems (CNICS) 队列，我们​​的团队确定了预测炎症的独特炎症生物标志物 以性别特异性方式相关的临床事件。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起始是 受多不饱和脂肪酸 (PUFA) 和类二十烷酸的产物控制，这是最具特征的 生物活性 PUFA 衍生物，通过调节血管张力、细胞张力在 CVD 发病机制中发挥作用 再生和血栓形成。参与类二十烷酸产生的 COX 途径具有特殊的临床意义 相关性，因为它是用于治疗疼痛、发烧的非甾体抗炎药 (NSAID) 的主要目标 和炎症。质谱技术的最新进展使我们的团队能够量化数百种 两个非 HIV 群体血浆中的类二十烷酸并检测与 CVD 风险相关的特定途径，其中一些途径是 性别特定的方式。然而，血浆类二十烷酸在 PWH CVD 发病机制中的因果作用尚未明确。 已被阐明。因此，我们的目标是利用 CNICS 队列和已裁定的临床事件来 阐明类二十烷酸在感染者 CVD 风险中的作用。我们假设类二十烷酸具有炎症作用 HIV 相关 CVD 发病机制的介质，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，表征 PWH 的血浆类二十烷酸谱 控制并建立它们与 CVD 危险因素、HIV 相关因素（疾病持续时间、病毒载量、 3,000 名感染者的 CD4 计数）、性别和临床事件； 2. 评估类二十烷酸的因果推论 心血管事件并确定与 PWH 中类二十烷酸谱相关的独特遗传位点，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 感染者心血管风险的生物学途径和关键驱动因素，并确定新的或重新调整用途的干预措施 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、 对感染和未感染艾滋病毒的个体进行心血管疾病干预。