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.

项目概要 怀孕期间的母体炎症，定义为循环促炎细胞因子水平升高， 可能对后代神经发育产生不利影响，但其机制仍不清楚。 生物衰老被认为是产前暴露影响未来的潜在机制 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 迄今为止，儿科表观遗传学研究受到以下限制：（1）使用成人特异性或全年龄时钟； （2）由于儿科血液采集的挑战，扫描纵向表观遗传数据在这里，我们使用了新的方法。 开发了儿科专用时钟 [儿科颊表观遗传 (PedBE) 时钟]，可以使用 非侵入性口腔拭子，促进整个童年的重复测量。 测量婴儿和幼儿的生物标志物，反映其在怀孕期间暴露于母体炎症的情况 这项创新且具有成本效益的纵向研究可以预测怀孕和随后的发病风险。 研究将利用基础设施、生物样本库和经过严格表型分析的健康人群的现有数据 孕妇及其后代从妊娠早期到 4 岁（R01HD083369， UH3OD023349）。了解妊娠信号和婴儿发育（UPSIDE-ECHO）队列 包括对怀孕期​​间炎症的全面评估、重复测量 整个童年时期的神经发育、详细的心理、社会人口、临床和生活史数据， 以及 2015 年至 2024 年收集的丰富的生物样本库（我们的中心正在进行 3-4 岁的访问）。 假设认为，怀孕期间母体炎症会加速后代的表观遗传年龄，从而产生不利影响 我们的跨学科影响研究团队由妇幼专家组成。 在目标 1 中，我们将关注健康、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。 建立后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，我们将研究关联。 在目标 3 中，我们将探讨孕期炎症与后代表观遗传年龄加速之间的关系。 检查后代表观遗传年龄与 4 岁时神经认知之间的关联，并探讨是否 表观遗传年龄介导孕期炎症与神经认知之间的关联 本 R01 中提出的研究意义重大，因为它将产生对这种联系的新见解。 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，重点是 关于表观遗传年龄加速如何影响后代的神经认知，这项形成性工作将推进我们的研究。 了解表观遗传年龄轨迹在关键发育时期如何变化，并确定 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。