Advancing the science and technology of prenatal programing research

7.项目总结/摘要 儿童期身体、情绪和行为问题的发展起源开始于子宫内。产前 经验“程序”的情况下，婴儿/他将遇到出生时，奠定了健康的基础 结果和疾病。然而，产前环境与早期婴儿的生物学机制 结果仍然没有得到充分研究。将表观遗传学方法应用于人类行为是一个相对较新的研究领域。 致力于了解环境影响如何塑造基因表达的创新奋进 与DNA结构无关。怀孕期间暴露在极端压力下的婴儿表现出表观遗传 适应，与生物系统校准以准备高风险产后 环境迫切需要对表观遗传过程进行创新性的人类研究。有两个主要的差距 在文学作品中至今。首先，将母亲压力与表观遗传结果联系起来的机制仍然很差 明白其次，大多数表观遗传学研究只检查了少量的选择标记（即，少于 10)候选基因，而不是复杂的相互依赖的遗传网络。本提案的目的 是通过（1）确定母亲是否患有 情绪困扰的全部范围和仔细表征的母体应激反应（例如，自主神经和 神经内分泌）在实验室评估;和（2）开发一种新的，假设驱动的测定，以评估 基因网络中的表观遗传过程。这些基因是基于对以下基因的严格审查而选择的： 与HPA轴功能相关。符合研究领域标准（RDoC） 在这个框架下，母亲们将根据一系列情绪失调的分数进行筛选和登记。 (ED)措施艾德是一个重要的跨诊断漏洞，几乎与所有 精神病诊断，高压力暴露，养育困难，健康风险行为，以及代际 精神病理学的传播具体来说，我们将招募158位母亲，在艾德上均匀分布 措施，进行全面的实验室压力评估，测量胎盘的表观遗传结果， 样本，评估新生儿的行为结果，并开发与压力相关的表观遗传标记物的测定。 这个创新项目既全面又经济;它将一个一流的科学家团队与 设备，许多必要的用品，以及慷慨的机构支持，以进行拟议的 research.当这个项目的目标实现时，我们将对早期成果有更好的了解。 对于失调母亲的婴儿。我们还将创造一种新的测定方法， 复制以及与压力相关的表观遗传标记的新研究。这项短期的纵向研究 为进一步跟踪婴儿到幼儿期和研究的纲领性路线奠定了基础 致力于了解和干预失调的母亲和儿童，特别是那些在最高 需要更好的预防保健。

7. Project Summary/Abstract The developmental origins of childhood physical, emotional, and behavioral problems begin in utero. Prenatal experiences “program” the infant for the context s/he will encounter upon birth, laying a foundation for health outcomes and disease. However, the biological mechanisms linking the prenatal environment to early infant outcomes remain understudied. The application of epigenetic methods to human behavior is a relatively new and innovative endeavor devoted to understanding how environmental influences shape gene expression independent of DNA structure. Infants exposed to extreme stress during pregnancy show epigenetic adaptations, consistent with theories that biological systems calibrate in preparation for a high-risk postnatal environment. Innovative human research on epigenetic processes is sorely needed. There are two major gaps in the literature to date. First, the mechanisms linking maternal stress to epigenetic outcomes are still poorly understood. Second, most epigenetic studies only examine a small number of marks on select (i.e., fewer than 10) candidate genes, rather than a complex interdependent genetic network. The objective of this proposal is to advance the science and technology of prenatal programing research by (1) identifying mothers with the full range of emotional distress and carefully characterizing maternal stress reactivity (e.g., autonomic and neuroendocrine) in a laboratory assessment; and (2) developing a novel, hypothesis-driven assay to assess epigenetic processes within a network of genes. These genes were selected based on rigorous review of published associations with HPA axis functioning. Consistent with the Research Domain Criteria (RDoC) framework, mothers will be screened and enrolled based upon a range of scores on emotion dysregulation (ED) measures. ED is an important transdiagnostic vulnerability that has been linked to nearly every psychiatric diagnosis, high stress exposure, parenting difficulties, health-risk behaviors, and intergenerational transmission of psychopathology. Specifically, we will recruit 158 mothers with a uniform distribution on ED measures, conduct a thorough laboratory assessment of stress, measure epigenetic outcomes in placental samples, assess newborn behavioral outcomes, and develop an assay of stress-related epigenetic markers. This innovative project is both comprehensive and economical; it unites a stellar team of scientists with equipment, many of the necessary supplies, and generous institutional support to conduct the proposed research. When the aims of this project are realized we will have an improved understanding of early outcomes for infants of dysregulated mothers. We will also have created a novel assay, which will promote rapid replication as well as new investigations of stress-related epigenetic marks. This short-term longitudinal study lays the foundation for further follow-up of infants into early childhood and a programmatic line of research devoted to understanding and intervening with dysregulated mothers and children, especially those in highest need of improved preventative care.