Epigenetics in Neurodevelopment and Mental Health

描述（由申请人提供）：宫内环境对神经发育（包括精神疾病风险）的关键作用越来越清楚，尽管这种环境对精神病理的影响机制当然是复杂的，而且还没有得到很好的理解。我们的工作开始证明胎盘作为宫内环境的主要调节器，与大脑共享综合内分泌控制，可以在神经发育中发挥基本的功能作用。这一初步的工作促使了这项研究的开展，这项研究与NIMH的战略使命一致，旨在为宫内环境中生命早期经历的机制提供关键的见解，通过修改表观基因组，改变神经发育途径，并有助于后来的精神健康障碍。提出的研究是基于这样的假设：胎盘中的DNA甲基化模式改变了胎盘作为子宫内环境调节器的功能，因此将以与后期精神病理学发展相关的方式与婴儿神经发育相关。我们提出了一种多模式的转化研究方法，利用现有的、正在进行的基于人群的出生队列的人口资源，使用NICU网络神经行为量表（NNNS）进行验证的、前瞻性的、功能性的婴儿神经行为评估，以及最先进的方法来检查人类样本的表观遗传和表观基因组图谱。该项目的目的是：(1)使用NNNS识别胎盘中候选基因的DNA甲基化与出生时神经行为结果之间的关联；(2)使用NNNS测试胎盘常染色体基因特异性DNA甲基化与出生时神经行为结果相关的假设，并验证这些关联。(3)使用NNNS验证性别连锁位点以性别分层方式的基因特异性DNA甲基化谱与出生时神经行为结果相关的假设。这项研究的结果有可能扩大我们对心理健康发育起源的理解，并证明胎盘及其基因组的表观遗传控制在婴儿神经发育中的关键作用。在可接近的组织（如胎盘）中识别与行为轨迹改变相关的表观遗传特征可能具有重大的临床和公共卫生意义，为早期诊断工具提供了机会，可以指导有针对性的早期干预高危儿童。

DESCRIPTION (provided by applicant): The critical role of the intrauterine environment on neurodevelopment including mental disease risk is becoming increasingly clear, although the mechanisms through which this environment contributes to psychopathology is certainly complex and not well understood. Our work is beginning to demonstrate the fundamental functional role that the placenta, acting as a master regulator of the intrauterine environment and sharing integrated endocrine control with the brain, can play on neurodevelopment. This preliminary work has compelled this examination, which, in line with the strategic mission of the NIMH, aims to provide critical insights into the mechanisms through which the earliest of life's experiences in the intrauterine environment can, through modification of the epigenome, alter neurodevelopmental pathways and contribute to later mental health disorders. The proposed study is compelled by the hypothesis that the pattern of DNA methylation in the placenta acts to alter the function of the placenta as regulator of the intrauterine environment and thus will be associated with infant neurodevelopment in ways that relate to the later development of psychopathology. We propose a multi-modal, translational research approach, utilizing the population resources of an existing, ongoing population-based birth cohort, the validated, prospective, functional infant neurobehavioral assessments using the NICU Network Neurobehavioral Scale (NNNS), and state-of-the-art approaches for the examination of epigenetic and epigenomic profiles in human samples. The aims of this project are (1) to identify the association between DNA methylation of candidate genes in the placenta and neurobehavioral outcomes at birth using the NNNS (2) to test the hypothesis that profiles of gene-specific DNA methylation of autosomal loci in placenta are associated with neurobehavioral outcomes at birth using the NNNS and to validate these associations, and (3) to test the hypothesis that profiles of gene-specific DNA methylation of sex-linked loci in a sex-stratified manner are associated with neurobehavioral outcomes at birth using the NNNS. The results of this study have the potential to expand our understanding of the developmental origins of mental health, and demonstrate the key role of the placenta and the epigenetic control of its genome in infant neurodevelopment. Identification of an epigenetic signature associated with altered behavioral trajectories in an accessible tissue, such as the placenta, can have significant clinical and public health implications, providing an opportunity for early diagnostic tools which can direct targeted and early interventions for at-risk children.