Maternal inflammation in relation to offspring epigenetic aging and neurodevelopment

项目总结 妊娠期母体炎症，定义为循环促炎细胞因子水平升高， 会对后代的神经发育产生不利影响。然而，机制仍然难以捉摸。加速 生物衰老已被认为是产前暴露影响未来的潜在机制 健康。这个过程可以通过表观遗传时钟来评估，表观遗传时钟基于dna估计表观遗传年龄。 甲基化水平，被广泛用作测量表观遗传年龄的临床相关生物标记物 加速。到目前为止，儿科表观遗传学研究一直受到以下限制：(1)使用成人专用或全年龄时钟； (2)由于儿科采血的挑战，缺乏纵向表观遗传学数据。在这里，我们使用一个新的 开发了儿科专用时钟[儿科颊表观遗传学(PedBE)钟]，可以使用以下公式进行评估 非侵入性口腔拭子，便于在儿童时期重复采取措施。我们的长期目标是找出容易的- 测量婴儿和幼儿中反映母体炎症暴露的生物标志物 并预测后代随后发病的风险。这一创新且经济实惠的纵向 这项研究将利用基础设施、生物信息库和现有的数据，这些数据来自一组严格表型的健康人群 孕妇及其后代从怀孕前三个月一直跟踪到4岁(R01HD083369， UH3OD023349)。了解妊娠信号与婴儿发育(向上-回声)队列 包括对怀孕期间炎症的全面评估，重复测量 儿童时期的神经发育，详细的心理，社会人口，临床和生活史数据， 以及2015-2024年收集的丰富的生物标本储存库(3-4岁正在进行的访问)。我们的中央 假说是，怀孕期间的母体炎症会加速后代的表观遗传年龄，对此不利 影响神经发育。我们的跨学科研究团队由妇幼专家组成 健康、表观基因组学、免疫学、认知科学、围产期流行病学和生物统计学。在目标1中，我们将 建立子代表观遗传年龄从出生到4岁的纵向变化轨迹 确定与后代表观遗传年龄加速相关的因素。在目标2中，我们将学习联想 孕期母体炎症与子代表观遗传年龄加速之间的关系。在《目标3》中，我们将 检查后代表观遗传年龄和4岁之间的神经认知之间的关系，并探索 表观遗传年龄在孕期母体炎症与神经认知之间的关系中起中介作用 结果。本R01中提出的研究具有重要意义，因为它将对该联系产生新的见解 妊娠期母体炎症与加速衰老的基因组生物标记物之间的关系 关于加速的表观遗传年龄如何影响后代的神经认知。这项开创性的工作将推进我们的 理解表观遗传年龄轨迹在关键发育时期的变化，并确定 母体/子代干预的机会，以改善整个一生的神经认知结果。

PROJECT SUMMARY Maternal inflammation during pregnancy, as defined by elevated levels of circulating pro-inflammatory cytokines, can have adverse effects on offspring neurodevelopment. However, mechanisms remain elusive. Accelerated biological aging has been proposed as an underlying mechanism by which prenatal exposures influence future health. This process can be evaluated through epigenetic clocks, which estimate epigenetic age based on DNA methylation levels, and are widely used as clinically relevant biomarkers that measure epigenetic age acceleration. To date, pediatric epigenetic studies have been limited by: (1) use of adult-specific or all-age clocks; and (2) scant longitudinal epigenetic data due to challenges of pediatric blood collection. Here, we use a newly developed pediatric-specific clock [the pediatric buccal epigenetic (PedBE) clock] that can be evaluated using non-invasive buccal swabs, facilitating repeat measures across childhood. Our long-term goal is to identify easy- to-measure biomarkers in infants and young children that reflect exposure to maternal inflammation during pregnancy and predict subsequent risk for morbidity in offspring. This innovative and cost-effective longitudinal study will leverage the infrastructure, biorepository, and extant data of a rigorously phenotyped cohort of healthy pregnant women and their offspring followed from the first trimester through age 4 (R01HD083369, UH3OD023349). The Understanding Pregnancy Signals and Infant Development (UPSIDE-ECHO) cohort includes comprehensive assessments of inflammation across pregnancy, repeated measures of neurodevelopment across childhood, detailed psychological, sociodemographic, clinical, and life history data, and a rich repository of biospecimens collected from 2015 – 2024 (age 3-4 visits in progress). Our central hypothesis is that maternal inflammation during pregnancy accelerates the offspring’s epigenetic age, adversely influencing neurodevelopment. Our interdisciplinary research team is comprised of experts in maternal and child health, epigenomics, immunology, cognitive science, perinatal epidemiology, and biostatistics. In Aim 1, we will establish trajectories of longitudinal changes in offspring epigenetic age from birth through 4 years of age and identify factors associated with offspring epigenetic age acceleration. In Aim 2, we will study associations between maternal inflammation during pregnancy and offspring epigenetic age acceleration. In Aim 3, we will examine associations between offspring epigenetic age and neurocognition through age 4, and explore if epigenetic age mediates the association between maternal inflammation during pregnancy and neurocognitive outcomes. The research proposed in this R01 is significant because it will generate new insights into the link between maternal inflammation during pregnancy and genomic biomarkers of accelerated aging, with a focus on how accelerated epigenetic age can impact offspring neurocognition. This formative work will advance our understanding of how epigenetic age trajectories change across a critical developmental period and identify opportunities for maternal/offspring interventions to improve neurocognitive outcomes across the entire lifespan.