Placental DNA Methylation, Maternal Hardship and Child Neurodevelopmental Outcomes

项目摘要/摘要 这个应用程序的总体目标是建立DNA甲基化、母体困难和 极早产儿的神经发育障碍。中心假设是产妇的困难 神经丛与神经发育结果有关，特别是认知和情感障碍。 这种关系是通过胎盘DNA甲基化来调节的。这项研究 将检查从极低妊娠中抽取的极早产儿(N=889)的各种样本 新生儿年龄研究(Elgan，#1UG3OD023348-01)。ELGAN是一项多中心的风险纵向研究 极早产儿的神经功能障碍。我将结合现有的关于(1)产前产妇困难的数据； (2)胎盘标本的DNA甲基化；(3)神经发育障碍，特别是认知障碍 以及在2岁和10岁时的情感结果。此外，我将参与Elgan后续行动的第三阶段 收集15岁参与者的神经发育障碍数据。具体目标是：(1)建立 使用产前社会经济和应激性生活事件因素的产妇困难组；(2)确定 母亲困难群体与2岁、10岁和10岁儿童的认知和情感结果之间的关系 15年；以及(3)确定DNA甲基化在多大程度上调节母体之间的关系 艰难困苦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关于预防儿童时期有已知危险因素的慢性疾病的病因途径。我的研究 背景是护理，特别关注母亲的困难，少数民族的围产期情感症状和/或 其他易受伤害的母亲，以及相关的儿童结果。我的短期职业目标是将我的研究扩展到 将母亲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的教学、实践指导和沉浸在 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； 研究中负责任的行为；出版和出席会议。我已经组装了一个 由国际公认的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 护士领导进行纵向研究，预防或减少与以下疾病相关的神经发育损害 处于危险中的儿童中的产妇困难。我随后的R01将探索更多的表观遗传途径 与艰辛有关。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，以确定可能 干预的潜在目标。

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.