Placental DNA Methylation, Maternal Hardship and Child Neurodevelopmental Outcomes

项目概要/摘要 该应用程序的总体目标是建立 DNA 甲基化、孕产妇困难和 极早产儿的神经发育障碍。中心假设是母亲的困难 集群与神经发育结果相关，尤其是认知和情感障碍。 极早产儿，这种关系是由胎盘中的 DNA 甲基化介导的。该研究 将检查从极低妊娠儿组中抽取的极早产儿的不同样本 (N = 889) 新生儿年龄研究（ELGAN，#1UG3OD023348-01）。 ELGAN 是一项针对以下风险的多中心纵向研究： 极早产儿的神经系统疾病。我将结合现有数据（1）产前母亲的困难； (2)胎盘标本DNA甲基化； (3) 神经发育障碍，特别是认知障碍 以及 2 岁和 10 岁时的情感结果。此外，我将参与 ELGAN 后续的第三阶段 收集 15 岁时参与者的神经发育障碍数据。具体目标是 (1) 建立 利用产前社会经济和压力生活事件因素的孕产妇困难集群； (2) 识别 产妇困难集群与 2 岁、10 岁和 2 岁儿童认知和情感结果之间的关联 15 年； (3) 确定 DNA 甲基化在多大程度上介导母体之间的关系 困难以及认知和情感结果。这项研究与 NINR 的创新问题密切相关 2.6 预防儿童期已知危险因素的慢性疾病的病因学途径。我的研究 背景是护理，特别关注产妇困难、少数群体的围产期情感症状和/或 其他弱势母亲以及相关的儿童结局。我的短期职业目标是将我的研究扩展到 将孕产妇的困难与高危儿童的表观遗传机制和神经发育结果联系起来。 拟议的培训活动将包括正式教学、实践指导和沉浸式研究 表观遗传学，儿童神经发育的生物学基础；大型跨学科团队的经验； 负责任的研究行为；以及出版物和出席会议的情况。我已经组装了一个 由国际知名专家组成的跨学科指导团队。这个奖项将使我走向独立 作为一名研究人员，支持我下一步获得资金，并帮助我实现成为一名研究人员的长期目标 纵向研究的护士领导者，旨在预防或尽量减少与以下疾病相关的神经发育障碍 高危儿童的产妇困难。我后续的 R01 将探索额外的表观遗传途径 与困难有关。我计划使用 NIH 环境对儿童健康结果影响的 35 个队列 （ECHO 计划；到 2019 年约 40,000 名儿童），其中包括 ELGAN，以确定可改变的因素 干预措施的潜在目标。

PROJECT SUMMARY/ABSTRACT The overall goal of this application is to establish relationships among DNA methylation, maternal hardship and neurodevelopmental impairment in extremely preterm children. The central hypothesis is that maternal hardship clusters are associated with neurodevelopmental outcomes, especially cognitive and affective impairment, in extremely preterm children and that this relationship is mediated by DNA methylation in the placenta. The study will examine a diverse sample of extremely preterm children (N = 889) drawn from the Extremely Low Gestational Age Newborns Study (ELGAN, #1UG3OD023348-01). ELGAN is a multi-center longitudinal study of the risk of neurologic disorders in extremely preterm children. I will combine existing data on (1) prenatal maternal hardship; (2) DNA methylation from placental specimens; and (3) neurodevelopmental impairment, specifically cognitive and affective outcomes at ages 2 and 10. Furthermore, I will be involved in the third phase of ELGAN follow-up to collect neurodevelopmental impairment data on participants at age 15. The Specific Aims are to (1) Establish maternal hardship clusters using prenatal socioeconomic and stressful life events factors; (2) Identify associations between maternal hardship clusters and child cognitive and affective outcomes at ages 2, 10 and 15 years; and (3) Determine the extent to which DNA methylation mediates the relationship between maternal hardship and cognitive and affective outcomes. This research aligns closely with NINR’s Innovative Question 2.6 on etiological pathways to prevent chronic illnesses with known risk factors in childhood. My research background is in nursing, with specific foci of maternal hardship, perinatal affective symptoms in minority and/or other vulnerable mothers, and related child outcomes. My short-term career goal is to expand my research to link maternal hardship to epigenetic mechanisms and neurodevelopmental outcomes among at-risk children. The proposed training activities will include formal didactic, hands-on instruction and research immersion in epigenetics, the biological bases of child neurodevelopment; experience in large interdisciplinary teams; responsible conduct in research; and publications and attendance at conferences. I have assembled an interdisciplinary mentoring team of internationally recognized experts. This award will move me to independence as a researcher, support my next steps in securing funding, and help me achieve my long-term goal of becoming a nurse leader in longitudinal research to prevent or minimize neurodevelopmental impairment related to maternal hardship among at-risk children. My subsequent R01 will explore additional epigenetic pathways related to hardship. I plan to use the 35 cohorts of the NIH Environment influences on Child Health Outcomes (ECHO Program; ~ 40,000 children by 2019), which includes ELGAN, to identify modifiable factors that could be potential targets for interventions.