Epigenetic Markers, Trajectories and Predictors of Neurodevelopment in Childhood among Infants Born Very Preterm

项目摘要 早产儿在儿童期经历不良发育结局的风险增加， 给这些婴儿及其家庭带来了沉重的负担。行为学领域的最新研究进展 表观基因组学表明，早产可能会对表观遗传调控产生长期影响， 不同的DNA甲基化与认知和行为功能的可变性有关。然而，有一点是缺乏的 已发表文献中的纵向表观基因组数据，因此尚不清楚是否与早产有关 表观基因组变异在儿童时期是持久的，或者如果早期生活中的表观基因组差异预示着以后的话 发展成果。DNA甲基化也可以用来估计表观遗传年龄加速 作为成人退行性疾病的潜在危险因素，已受到越来越多的关注。然而，在那里 有一些证据表明，表观遗传衰老可能与儿童时期的积极发育特征有关。 用我们之前的奖项(R01 HD084515-01A1)的资金，我们研究了早期生活与 与DNA甲基化和表观遗传年龄有关的医疗并发症和神经行为，确定了许多 在我们的早产儿队列中有显著的关系(NOVI)。然而，这些研究是横断面的。 在自然界中，应该对表观基因组数据进行重复测量。诺维的队列也是 入选美国国立卫生研究院环境对儿童健康结局影响(ECHO)联盟 (UG3 OD23347)，并被选中进入下一阶段的奖项(UH3 OD23347)，该阶段提供 资助我们7岁以下儿童的广泛表型特征，包括许多 神经发育评估。因此，我们提议在以前工作的基础上进行竞争性更新 并利用通过ECHO获得的广泛和高质量的结果数据。我们提出了一个 严格表型的婴儿队列中DNA甲基化和表观遗传老化的纵向研究 早产(妊娠30周)。我们的目标是研究新生儿医疗并发症和 神经行为反应影响儿童时期DNA甲基化和表观遗传衰老的轨迹，以及 无论这些轨迹是与神经发育轨迹跟踪，还是对后来的损伤提供信息。 我们还致力于开发一种算法，将儿童表观遗传因素与其他已知风险结合起来 提高对哪些婴儿发育风险最高的预测精度的因素 减损。我们的研究的成功完成将提供新颖而丰富的数据来展示早期的 早产儿的生活经历对DNA甲基化和表观遗传老化模式的影响 儿童时期，表征这些表观遗传因素是如何与后来的发育结果联系在一起的，并提供 这是一种预测性工具，可以识别处于最大风险的儿童以后的发育障碍。

Project Summary Infants born very preterm are at increased risk of experiencing adverse developmental outcomes in childhood, resulting in substantial burdens for those infants and their families. Recent research in the field of behavioral epigenomics has indicated that preterm birth may have long term impacts on epigenetic regulation and that differential DNA methylation is linked to variability in cognitive and behavioral function. However, there is a lack of longitudinal epigenomic data in the published literature and thus it is unclear if preterm-associated epigenomic variations are persistent in childhood, or if epigenomic differences in early life are predictive of later developmental outcomes. DNA methylation can also be used to estimate epigenetic age acceleration which has received increasing attention as a potential risk factor for degenerative diseases in adults. However, there is some evidence that epigenetic aging may be related to positive developmental characteristics in childhood. With funds from our prior award (R01 HD084515-01A1), we studied the relationships between early life medical complications and neurobehavior with DNA methylation and epigenetic age, identifying numerous notable relationships in our cohort of very preterm infants (NOVI). However, these studies were cross-sectional in nature and should be followed up with repeated measure of epigenomic data. The NOVI cohort was also selected for inclusion in the NIH Environmental Influences on Child Health Outcomes (ECHO) consortium (UG3 OD23347) and selected to proceed to the next phase of the award (UH3 OD23347) which provides funding to support extensive phenotypic characterization of our children through age 7, including numerous neurodevelopmental assessments. Thus, we are proposing a competitive renewal to build on our prior work and leverage the extensive and high-quality outcome data being obtained through ECHO. We propose a longitudinal study of DNA methylation and epigenetic aging in a rigorously phenotyped cohort of infants that were born very preterm (< 30 weeks gestation). We aim to study how neonatal medical complications and neurobehavioral responses influence trajectories of DNA methylation and epigenetic aging in childhood, and whether these trajectories track with neurodevelopmental trajectories or are informative for later impairments. We also aim to develop an algorithm that incorporates childhood epigenomic factors with other known risk factors to improve the precision of predictions about which infants are at highest risk of developmental impairments. The successful completion of our study will provide novel and rich data demonstrating the early life experiences among very preterm infants that influence patterns of DNA methylation and epigenetic aging in childhood, characterize how those epigenetic factors are linked to later developmental outcomes, and provide a predictive tool to identify children that are at greatest risk later developmental impairment.