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： 尽管没有感染艾滋病毒，但暴露于艾滋病毒但未感染的儿童 (HEU) 的发病率较高 与未暴露于 HIV 的人 (HU) 相比，儿童期死亡率和心脏代谢结果更差 孩子们。 HEU 儿童在生命早期的免疫发育欠佳。这增加了他们患共病的风险 儿童期感染，并可能通过导致全身炎症增加而加剧心脏代谢风险 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 功能障碍始于生命早期，并已确定生命早期感染是全身炎症和 儿童期促动脉粥样硬化代谢特征的发展。因此，早期感染负担较高 HEU 儿童的生活可能代表了 HEU 发病机制中重要且尚未探索的途径。 心脏代谢功能障碍。在这项提案中，我们利用了 Drakenstein 儿童健康研究，这是一项良好的研究 HEU 和 HU 参与者的特征队列从出生起就进行跟踪，以调查 HIV 暴露和早期感染如何影响 生活中的感染会影响从出生到青春期早期代谢组的炎症反应变化， 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。目标 1 将描述从婴儿期到青春期早期的纵向代谢组轨迹 在不同发育阶段的 HEU (n=244) 和 HU (n=735) 儿童中使用 250 种代谢物。目的 2 将开发一套预测模型来识别儿童期（1 岁和 5 岁）的代谢组学特征，从而预测 心脏代谢功能障碍，包括较高的 BMI/肥胖、动脉僵硬度、血压、血脂异常和 青春期早期（10 岁）的胰岛素抵抗。目标 3 将评估生命早期感染之间是否存在关系 10 岁时的负担和代谢组学特征总体上由炎症途径和 HIV 介导 曝光状态。拟议的研究将为艾滋病毒领域做出重大贡献，提供一些 来自基于人群的 HEU 和 HU 参与者队列的第一个纵向代谢组数据来阐明 从婴儿期开始的心脏代谢功能障碍发展的分子途径。在 此外，该提案的研究结果通过识别代谢和炎症具有直接的临床意义 生命早期的生物标志物，以支持心脏代谢风险分层并告知未来是否需要进行干预 解决 HEU 心脏代谢健康问题应包括减少感染负担或严重程度。综合起来， 这项工作将提供新的机制数据和生物标志物识别，以告知 HEU 是否应该 成为儿童期筛查和干预工作的目标，以降低他们患心脏代谢疾病的风险。