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

极早产婴儿童年时期神经发育的表观遗传标记、轨迹和预测因子

• 批准号: 10462564
• 负责人: Todd M Everson
• 金额: $ 64.15万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462564
• 关键词: 37 weeks gestation; Acceleration; Adult; Adverse event; Affect; Age; Aging; Algorithms; Attention; Award; Behavioral; Birth; Cell Proliferation; Characteristics; Child; Child Health; Childhood; Chronology; Cognitive; Collection; Complex; DNA Methylation; Data; Degenerative Disorder; Development; Epigenetic Process; Exhibits; Family; Funding; Genes; Goals; Grant; Impaired cognition; Impairment; Infant; Life; Life Experience; Link; Literature; Live Birth; Longitudinal Studies; Longitudinal observational study; Lung; Maintenance; Measures; Medical; Methods; Methylation; Mood Disorders; Nature; Neonatal; Neonatal Intensive Care Units; Newborn Infant; Outcome; Pattern; Perinatal; Phase; Phenotype; Pregnancy; Premature Birth; Premature Infant; Psychosocial Factor; Public Health; Publishing; Research; Risk; Risk Factors; Role; Site; Structure; Time; United States National Institutes of Health; Variant; Work; autism spectrum disorder; behavioral impairment; biological development; cohort; early childhood; epigenetic marker; epigenetic regulation; epigenetic variation; epigenomics; experience; follow-up; genome-wide analysis; high risk; histone methyltransferase; improved; medical complication; neurobehavior; neurobehavioral; neurodevelopment; neurotransmission; novel; postnatal; predictive tools; programs; psychosocial; relating to nervous system; response; synaptic function

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.

项目概要 早产儿在童年时期经历不良发育结果的风险增加， 给这些婴儿及其家人造成沉重负担。行为学领域的最新研究 表观基因组学表明，早产可能对表观遗传调控产生长期影响，并且 DNA甲基化差异与认知和行为功能的变异性有关。然而，还存在不足 已发表文献中的纵向表观基因组数据，因此尚不清楚早产是否与 表观基因组变异在童年时期是持续存在的，或者如果早期生活中的表观基因组差异可以预测以后的情况 发展成果。 DNA 甲基化也可用于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，它受到越来越多的关注。然而，有 有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。 利用我们之前的奖项 (R01 HD084515-01A1) 的资金，我们研究了早期生活之间的关系 医学并发症和神经行为与 DNA 甲基化和表观遗传年龄相关，确定了许多 在我们的极早产儿队列 (NOVI) 中存在显着的关系。然而，这些研究是横断面的 在自然界中，应该重复测量表观基因组数据。 NOVI 队列还 入选 NIH 环境对儿童健康结果 (ECHO) 联盟的影响 (UG3 OD23347) 并被选中进入下一阶段的奖项 (UH3 OD23347)，该阶段提供 提供资金支持我们的孩子到 7 岁的广泛表型特征，包括许多 神经发育评估。因此，我们提议在我们之前的工作基础上进行竞争性更新 并利用通过 ECHO 获得的广泛且高质量的结果数据。我们提出一个 在严格表型的婴儿队列中进行 DNA 甲基化和表观遗传衰老的纵向研究 非常早产（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 这些轨迹是否与神经发育轨迹相符，或者是否为以后的损伤提供信息。 我们还旨在开发一种算法，将儿童表观基因组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 损伤。我们研究的成功完成将提供新颖而丰富的数据来证明早期的研究 极早产儿的生活经历影响DNA甲基化和表观遗传衰老的模式 童年时期，描述这些表观遗传因素如何与以后的发育结果相关，并提供 一种预测工具，用于识别后期发育障碍风险最大的儿童。