Epigenetic dysregulation of inflammation linked to longitudinal cardiac toxicity in perinatal HIV infection

炎症的表观遗传失调与围产期 HIV 感染的纵向心脏毒性有关

• 批准号: 10570883
• 负责人: Michael Jay Corley
• 金额: $ 21.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570883
• 关键词: Adolescent; Adolescent and Young Adult; Adult; Age; Archives; Biological; Biological Markers; Blood; Blood specimen; Cardiac; Cardiac Myocytes; Cardiac health; Cardiometabolic Disease; Cardiotoxicity; Cell physiology; Cells; Chemicals; Child; Child Development; Childhood; Chronic; Cryopreservation; DNA; DNA Methylation; DNA Sequence; Data; Databases; Development; Disease; Drug Exposure; Echocardiography; Epigenetic Process; Exposure to; Functional disorder; Funding; Future; Gender; Gene Expression Regulation; Generations; Genes; HIV; HIV Infections; HIV-infected adolescents; HIV/AIDS; Health; Health Policy; Heart Abnormalities; Heart Injuries; Heritability; IL18 gene; IL8 gene; Immune; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intervention Trial; Knowledge; Left; Left Ventricular Function; Left ventricular structure; Life Cycle Stages; Link; Long-Term Effects; Longevity; Longitudinal Studies; Measures; Memory; Mitochondria; Mitotic; Modification; Myocardial dysfunction; Nucleic Acid Regulatory Sequences; Outcome; Participant; Pediatric HIV/AIDS Cohort Study; Perinatal; Peripheral Blood Mononuclear Cell; Public Health; Receptors, Tumor Necrosis Factor, Type II; Regulator Genes; Research; Shapes; Stress; Structure; Systems Biology; TNF gene; TNFRSF1B gene; United States National Institutes of Health; Ventricular; Youth; antiretroviral therapy; biobank; candidate identification; cardiometabolic risk; cardiovascular health; cell type; design; epigenetic marker; epigenome; genome-wide; heart function; heart imaging; immune function; imprint; intrauterine environment; lens; methylation pattern; mitochondrial dysfunction; monocyte; novel; novel marker; pathogen exposure; pediatric human immunodeficiency virus; perinatal HIV; rate of change; research study; risk variant; systemic inflammatory response; young adult

Project Summary This proposal will use archived longitudinal cardiac imaging data and blood biospecimens from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) to advance pediatric HIV/AIDS research by studying the interplay between epigenetic dysfunction of disease-critical immune cell monocytes and longitudinal cardiac structure and function in both perinatally infected adolescents and young adults living with HIV and HIV-exposed uninfected (HEU) individuals. Increasing evidence shows that children who perinatally acquired HIV and have been exposed to antiretroviral therapy (ART) throughout development have documented subclinical cardiac abnormalities and an increased risk for cardiometabolic diseases. Systemic immune inflammation and mitochondrial dysfunction have been linked to HIV/ART exposure and cardiac abnormalities in children living with HIV. Yet, there remains a limited understanding of the biological mechanisms by which perinatal HIV infection and longitudinal exposure to ART interact to alter immune cell function leading to progressive deleterious cardiac changes. The novel premise of the proposed study is that early exposure to HIV and longitudinal ART during childhood imprints a durable biological memory on the epigenome of proinflammatory immune cells, as characterized by increased levels of systemic inflammation and mitochondrial dysfunction related to progressive deleterious changes in left ventricular stress and cardiomyocyte damage. Using a systems biology approach, we will examine epigenetic profiles of enriched monocyte cells obtained from viably cryopreserved peripheral blood mononuclear cells (PBMCs) in 120 HIV+ adolescents and young adults with a mean ART exposure of 11.3 years and 80 HEU youth from an NIH supported PHACS sub study. Epigenetics data will be integrated with existing longitudinal echocardiographic data and biomarkers data for inflammation, cardiac injury, and mitochondrial function. Aim 1 will identify epigenetic features in purified monocytes associated with cardiac function and biomarkers in 120 HIV+ adolescents and young adults and 80 age/gender matched HEU participants of the Pediatric HIV/AIDS Cohort Study (PHACS). Aim 2 will evaluate whether changes in longitudinal echocardiographic measures over three years relate to differences in monocyte DNA methylation patterns. The study approach will both define the immune cell-type specific epigenomes of 120 HIV+ adolescents and young adults and 80 age/gender matched HEU adolescents and young adults and determine how longitudinal exposure to HIV/ART throughout development reshapes the immune cell epigenome leading to progressive cardiac dysfunction. Understanding the impacts of HIV/ART on subclinical cardiac abnormalities in adolescents and young adults living with HIV through the lens of epigenetics will be critical to identifying novel biomarkers of subclinical cardiac abnormalities and for informing public health policy and the design of future intervention trials aimed at optimizing cardiovascular health across the lifespan in children living with HIV.

项目摘要 该建议将使用NIH的存档纵向心脏成像数据和血液生物测量 小儿艾滋病毒/艾滋病队列研究（PHACS）通过研究相互作用来推动小儿艾滋病毒/艾滋病研究 疾病临界免疫细胞单核细胞的表观遗传功能障碍与纵向心脏结构之间 并在周围感染的青少年和艾滋病毒和艾滋病毒暴露的年轻人中发挥作用 未感染（HEU）的人。越来越多的证据表明，围绕艾滋病毒并具有的儿童 在整个发育中都暴露于抗逆转录病毒疗法（ART）已记录了亚临床心脏 异常和心脏代谢疾病的风险增加。系统性免疫炎症和 线粒体功能障碍与生活的儿童的艾滋病毒/艺术暴露和心脏异常有关 与艾滋病毒。然而，对围产期艾滋病毒的生物学机制仍然有限 感染和ART纵向暴露于ART相互作用以改变免疫细胞功能，导致进行性 有害心脏变化。拟议的研究的新前提是，早期暴露于艾滋病毒和 童年时期的纵向艺术在促炎性的表观中具有耐用的生物记忆 免疫细胞，其特征是全身炎症和线粒体功能障碍的水平升高 与左心室应激和心肌细胞损伤的进行性有害变化有关。使用 系统生物学方法，我们将检查从可通过的富集单核细胞的表观遗传谱 120 HIV+青少年和年轻人的冷冻保存外周血单核细胞（PBMC） 来自NIH支持PHACS Sub研究的11.3岁的平均艺术风险为11.3岁。表观遗传学 数据将与现有的纵向超声心动图数据和生物标志物数据集成，以进行炎症， 心脏损伤和线粒体功能。 AIM 1将识别纯化的单核细胞中的表观遗传特征 与120名HIV+青少年和年轻人的心脏功能和生物标志物以及80岁/性别相关 匹配小儿艾滋病毒/艾滋病队列研究（PHACS）的HEU参与者。 AIM 2将评估是否 三年内纵向超声心动图测量的变化与单核细胞DNA的差异有关 甲基化模式。研究方法都将定义120个免疫细胞类型的特异性表观基因组。 HIV+青少年和年轻人以及80岁/性别与HEU青少年和年轻人相匹配， 确定整个发育中对艾滋病毒/艺术的纵向暴露于重塑免疫细胞 表观基因组导致心脏功能障碍。了解艾滋病毒/艺术对亚临床的影响 通过表观遗传学镜头的青少年和年轻人的心脏异常将是 对于识别亚临床心脏异常的新型生物标志物以及通知公共卫生政策至关重要 以及未来干预试验的设计旨在优化整个生命周期的心血管健康 患有艾滋病毒的孩子。