Environment, Epigenetics, Neurodevelopment & Health of Extremely Preterm Children

项目概要/摘要 ECHO 联盟的目标是确定早期与环境相关的暴露和机制。 生命到儿童发展和健康结果。该提案致力于 ECHO 联盟 来自极低胎龄新生儿 (ELGAN) 研究的大量资源。自成立以来 2001 年，ELGAN 研究的总体目标是评估围产期炎症与 极早产个体（即出生 28 周之前）的神经发育障碍 妊娠）。在拟议的项目中，我们将在 ELGAN 研究成功的基础上添加新信息 关于：1) 环境暴露，2) 研究参与者 15 岁和 18 岁时的神经发育结果 年龄，以及3）胎盘表观遗传变异，一种可能将生命早期的炎症与 神经发育障碍。 在项目的前两年（UG3 阶段），来自 ELGAN 团队的研究人员将参与 设计可在 ECHO 联盟内实施并努力协调数据的研究 跨联盟组成的群体。在提案的第二年，我们将开始评估 ELGAN 队列的成员在年满 15 岁时，使用标准化的神经发育模型 评估和脑磁共振成像（MRI）。我们还将完成以下方面的初步研究 产前环境暴露、早期炎症和神经发育之间的关系 使用 ELGAN 队列的现有数据来评估损伤。此外，我们将完成表观遗传分析 ELGAN 研究参与者出生前后收集的胎盘标本中的标记。这些 数据将在拟议项目（UH3 阶段）的最后 5 年中使用。 如果达到预先指定的里程碑，该项目将过渡到 UH3 阶段。标准化 神经发育评估和脑磁共振成像（MRI）将作为研究完成 参与者年满15岁。当参与者年满 18 岁时，神经发育评估将再次进行 完成。在 18 岁时进行评估时，我们将采集血液用于研究激活的表观遗传标记 我们可以将其与生命早期系统性炎症的现有数据联系起来。 该项目 UH3 阶段的具体目标是检查早期生命生物标志物之间的关系 炎症（新生儿全身炎症的现有数据和胎盘表观遗传学的新数据）和 18 岁之前神经发育障碍。要解决的首要假设是 产前接触可能引发早期炎症，从而增加神经发育的风险 损伤。该项目的创新之处包括纵向视角、对胎盘的考虑 表观遗传学作为一种将产前暴露与儿童结局联系起来的机制，以及对广泛范围的评估 神经发育结果。这项研究有可能为治疗方法的开发提供信息 针对表观遗传过程来预防或改善认知障碍，从而提高生活质量 在美国，每年有 16,000 名极早产患者幸存。

Project Summary/Abstract The goal of the ECHO Consortium is to identify exposures and mechanisms that link the environment in early life to childhood development and health outcomes. This proposal commits to the ECHO Consortium numerous resources from the Extremely Low Gestation Age Newborn (ELGAN) Study. Since its initiation in 2001, the broad goal of the ELGAN Study is to evaluate the relationship between perinatal inflammation and neurodevelopmental impairments among individuals born extremely premature (i.e., before 28 weeks of gestation). In the proposed project we will build on the success of the ELGAN Study by adding new information about: 1) environment exposures, 2) neurodevelopmental outcomes of study participants at 15 and 18 years of age, and 3) placental epigenetic variation, a mechanism that could link inflammation early in life to neurodevelopmental impairments. In the first two years of the project (the UG3 phase) investigators from the ELGAN team will participate in the design of studies that can be implemented across the ECHO Consortium and in efforts to harmonize data across cohorts comprising the consortium. In the second year of the proposal, we will begin to evaluate members of the ELGAN cohort, as they reach 15 years of age, using standardized neurodevelopmental assessments and brain magnetic resonance imaging (MRI). We also will complete preliminary studies of relationships between prenatal environmental exposures, early life inflammation, and neurodevelopmental impairments, using extant data from the ELGAN cohort. In addition, we will complete analysis of epigenetic markers in placenta specimens collected around the time of the births of ELGAN Study participants. These data will be utilized in the last 5 years of the proposed project (the UH3 phase). If pre-specified milestones are met, the project will transition into the UH3 phase. Standardized neurodevelopmental assessments and brain magnetic resonance imaging (MRI) will be completed as study participants reach 15 years. As participants reach 18 years of age neurodevelopmental assessments will again be completed. At the assessment at 18 years we will obtain blood for study of epigenetic markers of activation of innate immunity, which we can then relate to our extant data about systemic inflammation early in life. Specific aims in the UH3 phase of the project are examine relationships between biomarkers of early life inflammation (extant data on neonatal systemic inflammation and new data on placenta epigenetics) and neurodevelopmental impairments through age 18 years. The over-arching hypothesis to be addressed is that prenatal exposures can initiate early life inflammation, thus increasing the risk of neurodevelopmental impairments. Innovative aspects of this project include its longitudinal perspective, consideration of placenta epigenetics as a mechanism linking prenatal exposures to childhood outcomes, and evaluation of a wide range of neurodevelopmental outcome. This research has the potential to inform the development of therapies targeting epigenetic processes to prevent or ameliorate cognitive disability, thereby improving the quality of life for 16,000 individuals who survive extremely premature birth each year in the United States.