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

项目摘要： 尽管未感染艾滋病毒，但接触艾滋病毒但未感染的儿童的发病率较高 与未暴露于HIV的儿童相比， 孩子高浓缩铀儿童在生命早期的免疫发育不佳。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 对代谢途径有负面影响我们的研究小组利用代谢组学来表征代谢 在生命早期开始的功能障碍，并已确定生命早期感染是全身性炎症的驱动因素， 儿童时期促动脉粥样硬化代谢谱的发展。因此，早期感染的负担较高， 高浓缩铀儿童的生活可能是高浓缩铀发病机制中重要的和未探索的途径。 心脏代谢功能障碍在这个提案中，我们利用了Drakenstein儿童健康研究，一个很好的- 从出生起就对高浓缩铀和高浓缩铀参与者进行了特征性队列研究，以调查艾滋病毒暴露和早期 生命感染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局的发展， 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学轨迹 使用不同发育阶段的高浓缩铀（n=244）和高浓缩铀（n=735）儿童中的250种代谢物。目的 2将开发一套预测模型，以确定儿童（1岁和5岁）的代谢组学特征， 心脏代谢功能障碍，包括BMI/肥胖、动脉僵硬度、血压、血脂异常和 胰岛素抵抗，在青春期早期（10年）。目标3将评估早期生命感染与 10岁时的负荷和代谢组学特征由炎症途径介导，总体上由HIV介导 暴露状态。这项拟议的研究将通过提供一些 来自HEU和HU参与者的基于人群的队列的第一个纵向代谢组学数据， 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，通过鉴别代谢和炎症，本提案的发现具有直接的临床相关性。 生命早期的生物标志物，以支持心脏代谢风险分层，并告知未来的干预措施是否 解决高浓缩铀患者的心脏代谢健康问题应包括减少感染负担或严重程度。综合起来看， 这项工作将提供新的机理数据和生物标志物鉴定， 在儿童时期进行筛查和干预工作，以降低他们患心脏代谢疾病的风险。

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.