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

基本信息

批准号：
10483606
负责人：
Michael Jay Corley
金额：
$ 28.58万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-11 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483606
关键词：
AIDS/HIV problem Adolescent Adolescent and Young Adult Adult 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 antiretroviral HIV-infected adolescents Health Health Policy Heart Abnormalities Heart Injuries Heritability IL8 gene Immune Individual Inflammation Inflammatory Interleukin-1 beta Interleukin-10 Interleukin-18 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 Regulator Genes Research Stress Structure Systems Biology TNF gene TNFRSF1B gene United States National Institutes of Health Ventricular Youth antiretroviral therapy biobank 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

项目摘要

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.

项目概要该提案将使用 NIH 存档的纵向心脏成像数据和血液生物样本儿科艾滋病毒/艾滋病队列研究 (PHACS) 通过研究相互作用来推进儿科艾滋病毒/艾滋病研究疾病关键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对围产期感染艾滋病毒的青少年和年轻成人以及艾滋病毒暴露者的作用未感染的（HEU）个体。越来越多的证据表明，围产期感染艾滋病毒的儿童在整个发育过程中接受抗逆转录病毒治疗（ART）已记录亚临床心脏病异常和心脏代谢疾病的风险增加。全身免疫炎症和线粒体功能障碍与 HIV/ART 暴露和儿童心脏异常有关患有艾滋病毒。然而，对于围产期艾滋病毒感染的生物学机制仍知之甚少。感染和纵向暴露于 ART 相互作用，改变免疫细胞功能，导致进行性有害的心脏变化。拟议研究的新颖前提是早期接触艾滋病毒和童年时期的纵向 ART 在促炎性表观基因组上留下了持久的生物记忆免疫细胞，其特征是全身炎症水平升高和线粒体功能障碍与左心室压力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，我们将检查从活体中获得的富集单核细胞的表观遗传谱冷冻保存的 120 名 HIV+ 青少年和年轻人的外周血单核细胞 (PBMC) 来自 NIH 支持的 PHACS 子研究的 11.3 年和 80 HEU 青年的平均 ART 暴露时间。表观遗传学数据将与现有的纵向超声心动图数据和炎症生物标志物数据整合，心脏损伤和线粒体功能。目标 1 将鉴定纯化单核细胞的表观遗传特征与 120 名 HIV+ 青少年和年轻人以及 80 名年龄/性别的心脏功能和生物标志物相关匹配了儿科艾滋病毒/艾滋病队列研究 (PHACS) 的 HEU 参与者。目标 2 将评估是否三年来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。该研究方法将定义 120 种免疫细胞类型特异性表观基因组 HIV+ 青少年和年轻人以及 80 名年龄/性别匹配的 HEU 青少年和年轻人以及确定在整个发育过程中纵向暴露于 HIV/ART 如何重塑免疫细胞表观基因组导致进行性心脏功能障碍。了解 HIV/ART 对亚临床的影响通过表观遗传学的视角，青少年和年轻人感染艾滋病毒的心脏异常将被对于识别亚临床心脏异常的新型生物标志物和为公共卫生政策提供信息至关重要以及旨在优化整个生命周期心血管健康的未来干预试验的设计感染艾滋病毒的儿童。