The Infants of Superstorm Sandy:The Epigenetic and Developmental Impact of Natural Disaster

描述（由申请人提供）：宫内时期对大脑发育至关重要，可能影响一生的心理健康。动物研究表明，怀孕期间的心理社会压力，特别是在怀孕的早期和中期，导致与次优中枢神经系统（CNS）发育相关的神经行为问题，涉及运动技能，唤醒，冲动和情绪失调。然而，这些研究不能直接应用于人类。拟议研究的总体目标是由以下假设驱动的：子宫内暴露于心理社会压力可以在胎儿发育的敏感窗口期间编程后代CNS功能的变化，导致神经发育障碍。这项研究建立在我们正在进行的NIH资助的研究，评估产前压力作为一个关键的神经发育风险因素。参与者（N=408）居住在皇后区/长岛，在那里“超级风暴桑迪”造成的破坏，使我们能够在怀孕期间进行压力的自然实验。利用现有的基础设施、已建立的生物储存库以及灾后桑迪相关创伤的前瞻性收集数据（严重程度，暴露时间，逆境持续时间和心理反应），和规范（来自日常生活）怀孕期间经历的心理社会压力，我们建议：1）通过对42个月大的后代进行跟踪，评估神经发育的关键区域与产前压力的关系; 2）评估暴露于桑迪创伤的时间是否与不同的神经发育轨迹相关; 3）探讨产前压力、儿童神经发育和表观/遗传的相互关系。（甲基化和基因表达）调节候选基因，包括胎盘和脐带血配对样本中的5个关键应激调节和神经发育途径，进一步探索这些基因的表观遗传调控是否诱导不同的神经发育轨迹; 4）探索儿童早期发育过程中表观遗传标记的稳定性。鉴于基因调控的独特生物学功能和组织和发育阶段特异性，出生时胎盘和脐带血以及儿童期唾液配对样本中的表观/遗传标记的评估有助于阐明疾病机制。通过展示在生命的不同时期收集外周组织的微创方法的实用性，该研究将推进未来流行病学研究的设计，并可能改善发育性精神病理学的预后和干预措施。使用结构方程模型，多级生长曲线模型和分层线性模型，我们将阐明在幼儿期次优神经发育的潜在机制，与母亲的心理社会压力暴露（类型，强度和时间）在怀孕过程中。这项研究最终将帮助我们绘制从子宫到出生和幼儿期的精神障碍过程， 进一步了解怀孕的关键时期及其对人类分子水平的影响，并为研究早期干预措施奠定基础，这些干预措施可以预防以后可能出现的精神障碍。

DESCRIPTION (provided by applicant): The intrauterine period is critically important for brain development and may influence mental health throughout life. Animal studies have shown that psychosocial stress during pregnancy, especially in early and mid-stages of gestation, lead to neurobehavioral problems associated with suboptimal Central Nervous System (CNS) development involving motor skills, arousal, impulsivity, and emotional dysregulation. Yet, these studies cannot be directly applied to humans. The overall goal of the proposed study is driven by the hypothesis that exposure to psychosocial stress in utero can program changes in the functioning of the offspring's CNS during sensitive windows of fetal development, leading to neurodevelopmental impairment. This study builds upon our on-going NIH-funded study which assesses prenatal stress as a critical neurodevelopmental risk factor. The participants (N=408) reside in Queens/Long Island, where "Superstorm Sandy" caused devastation, allowing us to conduct a natural experiment of stress during pregnancy. Capitalizing on existing infrastructure, an established biorepository, and prospectively collected data on Sandy-related trauma after the disaster (severity, timing of exposure, duration of adversity, and psychological reactions), and normative (from everyday life) psychosocial stress experienced during pregnancy, we propose to 1) follow offspring through 42 months of age to evaluate key areas of neurodevelopment as a function of their exposure to prenatal stress; 2) evaluate whether timing of exposure to Sandy trauma is associated with different neurodevelopmental trajectories; 3) examine the inter- relations of prenatal stress, child neurodevelopment, and epi/genetic (methylation and gene expression) regulation of candidate genes, encompassing 5 key stress modulation and neuro-development pathways in paired samples of placenta and cord blood, and further explore if epigenetic regulation in those genes induce different trajectories of neurodevelopment; 4) explore stability of epigenetic marks during early development in childhood. Given the distinct biological functions and tissue- and developmental stage-specificity of gene regulation, assessment of epi/genetic marks in paired samples of placenta and cord blood at birth and saliva in childhood could help clarify disease mechanism. By demonstrating the utility of less invasive ways to collect peripheral tissues at different times in life, the study will advance the design for future epidemiologic studies, and potentially improve prognosis and interventions for developmental psychopathology. Using structural equation modeling, multilevel growth curve modeling, and hierarchical linear models, we will elucidate the underlying mechanisms of suboptimal neurodevelopment in early childhood, in association with maternal psychosocial stress exposure (types, intensity, and timing) during the course of pregnancy. The study will ultimately help us chart the course of mental disorders from in utero to birth and early childhood, further our understanding of the critical periods of pregnancy and their effect on a molecular level in humans, and set the stage for research into early interventions that could preempt mental disorders that might emerge later in life.