Maternal inflammation in relation to offspring epigenetic aging and neurodevelopment

项目摘要 妊娠期间母体炎症，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 生物老化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，表观遗传时钟根据DNA估计表观遗传年龄 甲基化水平，并广泛用作测量表观遗传年龄的临床相关生物标志物 加速度迄今为止，儿科表观遗传学研究受到以下限制：（1）使用成人特异性或所有年龄的时钟; 和（2）由于儿科血液采集的挑战，纵向表观遗传数据不足。在这里，我们使用新的 开发了儿科特异性时钟[儿科口腔表观遗传（PedBE）时钟]，可以使用 非侵入性口腔拭子，便于在儿童期重复测量。我们的长期目标是识别简单的- 以测量婴儿和幼儿的生物标志物，反映在怀孕期间暴露于母体炎症。 妊娠和预测后代发病的后续风险。这种创新且具有成本效益的纵向 这项研究将利用基础设施，生物储存库和一个严格表型的健康队列的现存数据， 孕妇和她们的后代从最初的三个月一直跟踪到4岁（R 01 HD 083369， UH3OD 023349）。了解妊娠信号和婴儿发育（UPSIDE-ECHO）队列 包括对整个妊娠期炎症的全面评估， 儿童期的神经发育，详细的心理学、社会人口学、临床和生活史数据， 以及2015 - 2024年收集的丰富生物标本库（3-4岁访问正在进行中）。我们的中央 有一种假说认为，母亲在怀孕期间的炎症会加速后代的表观遗传年龄， 影响神经发育。我们的跨学科研究团队由母婴领域的专家组成， 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 建立从出生到4岁的后代表观遗传年龄的纵向变化轨迹， 确定与后代表观遗传年龄加速相关的因素。在目标2中，我们将研究关联 母亲怀孕期间的炎症和后代表观遗传年龄加速之间的关系。在目标3中，我们 检查后代表观遗传年龄和4岁之前的神经认知之间的关联，并探索 表观遗传年龄介导妊娠期母体炎症与神经认知功能之间的关联 结果。本R 01中提出的研究具有重要意义，因为它将对这种联系产生新的见解 怀孕期间母体炎症与加速衰老的基因组生物标志物之间的关系， 加速的表观遗传年龄如何影响后代的神经认知。这一形成性工作将推动我们的 了解表观遗传年龄轨迹如何在关键发育期发生变化， 母亲/后代干预的机会，以改善整个生命周期的神经认知结果。

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.