Early life determinants of cardiometabolic health from birth to adolescence amongst HIV-exposed and unexposed South African children

感染艾滋病毒和未感染艾滋病毒的南非儿童从出生到青春期心脏代谢健康的早期决定因素

• 批准号: 10547917
• 负责人: Angela Bengtson
• 金额: $ 62.2万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547917
• 关键词: 10 year old; Address; Adolescence; Affect; Amino Acids; Bioinformatics; Biological; Biological Markers; Biological Specimen Banks; Birth; Blood Pressure; Branched-Chain Amino Acids; Cardiometabolic Disease; Cardiovascular system; Child; Child Health; Childhood; Cholesterol; Climacteric; Clinical Data; Communicable Diseases; Data; Development; Dyslipidemias; Elderly; Evaluation; Exposure to; Fatty Acids; Functional disorder; Future; HIV; Health; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Insulin Resistance; Intervention; LDL Cholesterol Lipoproteins; Lead; Life; Mediating; Mediation; Metabolic; Metabolic Pathway; Metabolic dysfunction; Molecular; Morbidity - disease rate; Obesity; Outcome; Participant; Pathogenesis; Pathway interactions; Pediatric epidemiology; Perinatal Epidemiology; Plasma; Positioning Attribute; Puberty; Risk; Risk Factors; Sampling; Severities; South Africa; South African; Time; Triglycerides; Work; acylcarnitine; arterial stiffness; biological sex; biomarker identification; cardiometabolic risk; cardiometabolism; clinical application; clinically relevant; cohort; comorbidity; diabetogenic; disorder risk; early adolescence; experience; high body mass index; high risk; improved; infancy; infection burden; infection risk; inflammatory marker; metabolic profile; metabolome; metabolomics; microbiome; modifiable risk; mortality; novel; peri-urban; population based; predictive modeling; prospective; risk stratification; screening; systemic inflammatory response; urban area

PROJECT ABSTRACT: Despite not living with HIV, HIV-exposed but uninfected (HEU) children experience higher levels of morbidity and mortality in childhood and have worse cardiometabolic outcomes, compared to HIV-unexposed (HU) children. HEU children have suboptimal immune development in early life. This increases their risk for comorbid infections in childhood, and may exacerbate cardiometabolic risk by leading to increased systemic inflammation that adversely impacts metabolic pathways. Our group has used metabolomics to characterize metabolic dysfunction starting in early life and have identified early life infections as a driver of systemic inflammation and the development of pro-atherogenic metabolic profiles in childhood. Thus, the higher burden of infections in early life among HEU children may represent and important and unexplored pathway in the pathogenesis of cardiometabolic dysfunction. In this proposal, we leverage the Drakenstein Child Health Study, a well- characterized cohort of HEU and HU participants followed from birth, to investigate how HIV-exposure and early life infections affect inflammatory response changes to the metabolome from birth to early adolescence, and evaluate how these changes influence the development of adverse cardiometabolic outcomes in early adolescence. Aim 1 will characterize longitudinal metabolomic trajectories from infancy to early adolescence using 250 metabolites among HEU (n=244) and HU (n=735) children over different developmental stages. Aim 2 will develop a set of predictive models to identify metabolomic profiles in childhood (1 and 5 years) that predict cardiometabolic dysfunction, including higher BMI/adiposity, arterial stiffness, blood pressure, dyslipidemia, and insulin resistance, in early adolescence (10 years). Aim 3 will evaluate if relationships between early life infection burden and metabolomic profiles at 10 years of age are mediated by inflammatory pathways, overall and by HIV exposure status. The proposed study will make significant contributions to the field of HIV by providing some of the first longitudinal metabolomic data from a population-based cohort of HEU and HU participants to elucidate the molecular pathways underlying the development of cardiometabolic dysfunction starting in infancy. In addition, findings from this proposal have direct clinical relevance by identifying metabolic and inflammatory biomarkers in early life to support cardiometabolic risk stratification and inform whether future intervention efforts to address cardiometabolic health in HEU should include reducing infection burden or severity. Taken together, this work will provide novel mechanistic data and biomarker identification that will inform whether HEU should be targeted for screening and intervention efforts in childhood to reduce their risk of cardiometabolic disease.

项目摘要： 尽管没有艾滋病毒，但艾滋病毒暴露但未感染的（heu）儿童的发病率更高 与艾滋病毒无暴露（HU）相比 孩子们。 HEU儿童在早期生命中具有次优的免疫发育。这增加了他们合并的风险 儿童期感染，并可能通过增加全身性炎症来加剧心脏代谢风险 这会对代谢途径产生不利影响。我们的小组使用代谢组学来表征代谢 功能障碍从早期开始，并确定早期生活感染是系统性炎症和 童年时代的亲雄源性代谢特征的发展。因此，早期感染负担更高 在HEU儿童中的生活可能代表着重要而未开发的途径 心脏代谢功能障碍。在该提案中，我们利用Drakenstein儿童健康研究，这是一个很好的 特征是HEU和HU参与者从出生开始的人群，以调查艾滋病毒的暴露和早期暴露 生命感染会影响从出生到青春期早期对代谢组的炎症反应变化，并且 评估这些变化如何影响早期不良心脏代谢结果的发展 青春期。 AIM 1将表征从婴儿期到青春期早期的纵向代谢组轨迹 在不同的发育阶段，在HEU（n = 244）和HU（n = 735）儿童中使用250个代谢物。目的 2将开发一组预测模型，以识别童年（1和5年）的代谢组学特征 心脏代谢功能障碍，包括较高的BMI/肥胖，动脉僵硬，血压，血脂异常和 青春期早期（10年）的胰岛素抵抗。 AIM 3将评估早期生命感染之间的关系是否 10岁的负担和代谢组概况由炎症途径，整体和艾滋病毒介导 曝光状态。拟议的研究将通过提供一些 来自HEU和HU参与者的第一个纵向代谢组数据，以阐明 从婴儿期开始的心脏代谢功能障碍发展的基础的分子途径。在 此外，该提案的发现通过鉴定代谢和炎症具有直接的临床相关性 早期生命的生物标志物支持心脏代谢风险分层，并告知未来的干预工作 为了解决HEU中的心脏代谢健康，应包括减轻感染负担或严重程度。在一起， 这项工作将提供新颖的机械数据和生物标志物识别，这些数据将告知HEU是否应该 针对儿童期筛查和干预工作，以降低其心脏代谢疾病的风险。