Placental DNA Methylation, Maternal Hardship and Child Neurodevelopmental Outcomes

项目总结/摘要 该应用程序的总体目标是建立DNA甲基化，母亲困难和 极早产儿的神经发育障碍。核心假设是母亲的痛苦 集群与神经发育结果相关，特别是认知和情感障碍， 这种关系是由胎盘中的DNA甲基化介导的。研究 我将研究一个来自极低生育率地区的极早产儿（N = 889）的多样化样本。 年龄新生儿研究（ELGAN，#1UG3OD 023348 -01）。ELGAN是一项多中心纵向研究， 极早产儿的神经系统疾病我将联合收割机现有的数据（1）产前产妇的困难; (2)来自胎盘样本的DNA甲基化;和（3）神经发育障碍，特别是认知障碍 和情感的结果。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压力生活事件因素的孕产妇困难集群;（2）识别 母亲的困难集群和儿童在2岁，10岁和12岁时的认知和情感结果之间的关联 （3）确定DNA甲基化在多大程度上介导了母亲与母亲之间的关系。 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关于病因学途径，以预防儿童时期具有已知风险因素的慢性疾病。我的研究 背景是在护理，与产妇的困难，围产期的少数民族和/或情感症状的具体焦点， 其他弱势母亲，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; 负责任地进行研究;出版物和出席会议。我召集了一个 由国际知名专家组成的跨学科指导团队。这个奖会让我走向独立 作为一名研究人员，支持我获得资金的下一步，并帮助我实现成为一名 在纵向研究，以防止或尽量减少神经发育障碍有关的护士领导 高危儿童中的母亲困难。我接下来的R 01将探索更多的表观遗传途径 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，以确定可能影响儿童健康的可改变因素。 潜在的干预目标。

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.