Maternal inflammation in relation to offspring epigenetic aging and neurodevelopment

与后代表观遗传衰老和神经发育相关的母体炎症

• 批准号: 10637981
• 负责人: Stephanie Shiau
• 金额: $ 71.76万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637981
• 关键词: 4 year old; Acceleration; Adult; Adverse effects; Affect; Age; Aging; Animals; Anxiety; Biological Aging; Biological Markers; Biological Specimen Banks; Biometry; Birth; Blood; Body mass index; C-reactive protein; Child; Childhood; Chronology; Clinical; Cognitive; Cognitive Science; Collection; DNA Methylation; Data; Development; Elderly; Environment; Epigenetic Process; Exposure to; Fetus; First Pregnancy Trimester; Future; Gestational Age; Goals; Health; IL8 gene; Immunology; Impaired cognition; Infant; Infant Development; Inflammation; Inflammatory; Infrastructure; Intelligence; Interdisciplinary Study; Interferon Type II; Interleukin-1 beta; Interleukin-2; Interleukin-6; Intervention; Knowledge; Link; Longevity; Longitudinal Studies; Maternal Age; Maternal and Child Health; Measures; Mediating; Methylation; Molecular; Morbidity - disease rate; Neurocognition; Neurocognitive; Neurodevelopmental Disorder; Obesity; Outcome; Perinatal Epidemiology; Phenotype; Poverty; Pregnancy; Pregnancy Trimesters; Pregnant Women; Process; Reporting; Research; Risk; Signal Transduction; Specimen; Stress; Swab; TNF gene; Testing; Translating; Trauma; United States National Institutes of Health; Visit; Wechsler Scales; Work; adverse outcome; bead chip; biobank; clinical epidemiology; clinically relevant; cohort; cost effective; cost efficient; critical developmental period; cytokine; early childhood; epidemiology study; epigenomics; executive function; fetal; genomic biomarker; human old age (65+); improved; in utero; infancy; innovation; insight; life history; neurodevelopment; novel; offspring; prenatal; prenatal exposure; prepregnancy; psychologic; sex; sociodemographics; systemic inflammatory response; young adult

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.

项目摘要 孕妇在怀孕期间的炎症，这是由循环促炎细胞因子水平升高的定义， 可能对后代神经发育产生不利影响。但是，机制仍然难以捉摸。加速 已经提出生物衰老是一种基本机制，产前暴露会影响未来 健康。可以通过表观遗传钟来评估此过程，该表观时钟基于DNA估计表观遗传年龄 甲基化水平，被广泛用作临床相关的生物标志物，以测量表观遗传年龄 加速度。迄今为止，小儿表观遗传学研究受到以下限制：（1）使用成人特异性或全年时钟； （2）由于小儿血液收集的挑战，纵向表观遗传学数据很少。在这里，我们使用新的 开发的儿科特异性时钟[小儿颊表观遗传（PEDBE）时钟]可以使用 非侵入性颊拭子，支持整个童年的重复测量。我们的长期目标是确定容易 - 婴儿和幼儿的生物标志物反映了在 怀孕并预测后代发病率的随后风险。这种创新且具有成本效益的纵向 研究将利用严格表现的健康队列的基础设施，生物座位和现有数据 孕妇及其后代从头三个月到4岁（R01HD083369， UH3OD023349）。了解怀孕信号和婴儿发育（上回波）队列 包括对整个怀孕的炎症的全面评估，重复措施 整个童年的神经发育，详细的心理，社会人口统计学，临床和生活史数据， 以及从2015年至2024年收集的丰富的生物测量存储库（3-4岁的访问）。我们的中心 假设是，怀孕期间的孕产妇炎症加速了后代的表观遗传年龄，不利 影响神经发育。我们的跨学科研究团队完成了孕产妇和儿童专家 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AIM 1中，我们将 建立从出生到4岁的后代表观遗传年龄的纵向变化的轨迹 确定与后代表观遗传年龄加速有关的因素。在AIM 2中，我们将研究协会 在怀孕期间的伴生炎症与后代表观遗传年龄加速之间。在AIM 3中，我们将 检查后代表观遗传年龄与至4岁之间的神经认知之间的关联，并探索是否存在 表观遗传时代介导了怀孕期间的伴生炎症与神经认知之间的关联 结果。 R01中提出的研究很重要，因为它将对链接产生新的见解 在怀孕期间的孕产妇炎症与加速衰老的基因组生物标志物之间，重点 关于加速遗传年龄如何影响后代神经认知。这项形成性的工作将推动我们的 了解表观遗传年龄轨迹如何在关键的发展时期发生变化并确定 产妇/后代干预措施改善整个生命周期的神经认知结果的机会。