Epigenomic mechanisms of risk and resilience: The role of parenting

项目摘要 西班牙裔青年在发育、行为或社交方面的高风险几乎是其他人的三倍。 与白色非西班牙裔儿童相比，造成这种风险差异的原因是， 生活在贫困中的西班牙裔儿童和暴露于早期生活环境逆境的风险增加， 其赋予精神病理学发展的实质性风险和慢性疾病的终身风险。 早期逆境的不成比例的经历可能会影响风险的一个关键过程， 后来的精神病理学的发展是通过逆境暴露的生物嵌入， 参与神经内分泌和炎症反应的基因对应激反应的变化。尽管 风险过程的社会表观基因组学研究的前景和进展，现存的 文学是一个基本的了解如何生物嵌入逆境可以防止或逆转 尚未实现，对影响这些发展的保护因素的作用知之甚少 轨迹事实上，之前在人类身上的工作几乎完全是横截面的， 有害的环境影响，极大地限制了我们对表观基因组过程的理解 以及它对干预的积极延展性。拟议的研究将利用正在进行的NIH资助的R01 （#HD084497）通过一项基于家庭的行为父母培训的随机对照试验， 干预，如何改变社会背景（即，不健全的父母）改变了高危人群的表观基因组， 西班牙裔学龄前儿童，并可能建立一个生物基础，促进弹性， 潜在地改善了逆境的生物嵌入。在目前的建议中，我们建议使用 平衡的分析方法，包括（1）假设驱动的途径分析基因参与 神经内分泌和炎症反应的压力，（2）有针对性的设计，拉网站先前 在有力的EWAS研究中确定，以创建多表观遗传风险评分，以及（3）无假设 表观基因组关联研究除了检查儿童DNA甲基化的变化轨迹外， 我们将确定是否暴露于保护因素（积极的养育）缓冲逆境的影响， 在敏感的发育阶段加速老化的生物标志物。最后，我们将探索表观基因组学 基于儿童和父母DNA甲基化的早期干预反应的生物特征。为了所有的目的， 我们将使用多信息，多方法设计，包括观察养育，基于任务的 儿童自我调节的措施，儿童发展和临床结果的标准化评估， 独立的临床评估者，以及孩子和父母的DNA甲基化。这项研究将有助于 通过识别早期癌症的表观基因组生物标志物， 干预反应模式，这将允许在风险识别和个性化的创新战略 预防，共同导致对减少健康差距的有效方法的新理解。

Project Summary Hispanic youth are nearly three times more likely to be at high risk for developmental, behavioral, or social delays compared to white non-Hispanic children. Contributing to this risk disparity is disproportionate rates of Hispanic children living in poverty and heightened risk for exposure to early-life environmental adversity, all of which confers substantial risk for the development of psychopathology and a lifelong risk for chronic diseases. A critical process by which disproportionate experiences of early adversity might influence risk for the development of later psychopathology is through the biological embedding of adversity exposure via epigenetic changes in genes involved in neuroendocrine and inflammatory responses to stress response. Despite promise and progress of social epigenomic research on risk processes, a significant limitation of the extant literature is that a basic understanding of how biological embedding of adversity can be prevented or reversed has yet to be achieved, with little knowledge of the role of protective factors that impact these developmental trajectories. In fact, prior work in humans has been almost exclusively cross-sectional and focused on detrimental environmental impacts, greatly constraining our understanding of epigenomic processes over time and its positive malleability to interventions. The proposed research will leverage an on-going NIH-funded R01 (#HD084497) to evaluate, via a randomized controlled trial of a home-based behavioral parent training intervention, how changing social context (i.e., dysfunctional parenting) alters the epigenome among at-risk Hispanic preschoolers and potentially establishes a biological foundation that promotes resiliency and potentially ameliorates the biological embedding of adversity. In the current proposal, we propose to use a balanced analytical approach that includes (1) a hypothesis-driven pathway analyses for genes involved in neuroendocrine and inflammatory responses to stress, (2) a targeted design that pulls sites previously identified in well-powered EWAS studies to create poly-epigenetic risk scores, and (3) a hypothesis-free epigenome-wide association study. In addition to examining trajectories of change in child DNA methylation, we will determine if exposure to a protective factor (positive parenting) buffers the impact of adversity on biomarkers of accelerated aging during a sensitive developmental stage. Lastly, we will explore epigenomic biosignatures of response to early intervention based on both child and parent DNA methylation. For all aims, we will use a multi-informant, multi-method design that includes observations of parenting, task-based measures of child self-regulation, standardized assessments of child developmental and clinical outcomes, independent clinical evaluators, and both child and parent DNA methylation. This research will facilitate the application of precision medicine and prevention approaches by identifying epigenomic biomarkers of early intervention response patterns that will allow for innovative strategies in risk identification and personalized prevention, together resulting in a new understanding of effective approaches to reducing health disparities.