Epigenomic mechanisms of risk and resilience: The role of parenting

项目摘要 西班牙裔青年患发育、行为或社交疾病的风险几乎高出三倍 与非西班牙裔白人儿童相比，孩子们的发育迟缓。造成这种风险差异的原因是不成比例的 西班牙裔儿童生活在贫困中，早年暴露在环境逆境中的风险增加，所有这些 这给精神病理学的发展带来了巨大的风险，并成为慢性病的终身风险。 早期逆境中不成比例的经历可能影响风险的关键过程 后来的精神病理学的发展是通过表观遗传学的逆境暴露的生物学嵌入 应激反应中神经内分泌和炎症反应相关基因的变化。尽管 风险过程的社会表观经济学研究的前景和进展，这是现有风险过程的一个重大限制 文献是对如何防止或扭转逆境的生物性嵌入的基本理解 尚未实现，对影响这些发育的保护性因素的作用知之甚少 轨迹。事实上，之前在人类身上的研究几乎完全是横截面的，并集中在 有害的环境影响，随着时间的推移极大地限制了我们对表观基因组过程的理解 以及它对干预措施的积极延展性。拟议的研究将利用NIH资助的正在进行的R01 (#HD084497)通过一项基于家庭的行为父母培训的随机对照试验进行评估 干预，不断变化的社会环境(即，功能失调的父母)如何改变高危人群的表观基因组 西班牙裔学龄前儿童，并有可能建立一个生物基础，以促进弹性和 潜在地改善了逆境的生物嵌入性。在当前的提案中，我们建议使用 平衡分析方法，包括(1)假说驱动的基因通路分析 对应激的神经内分泌和炎症反应，(2)先前拉动部位的靶向设计 在强大的EWAS研究中确定，以创建多表观遗传风险分数，以及(3)无假说 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， 我们将确定暴露在保护性因素(积极的父母教育)下是否缓冲了逆境对 敏感发育阶段加速衰老的生物标志物。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。为了所有的目标， 我们将使用多信息者、多方法设计，其中包括对父母的观察，基于任务 儿童自我调节措施，儿童发展和临床结果的标准化评估， 独立的临床评估人员，以及儿童和父母的DNA甲基化。这项研究将有助于 精准医学的应用及早期表观基因组标志物的识别与预防 干预应对模式，将允许在风险识别和个性化方面采取创新战略 预防，共同导致对缩小健康差距的有效办法有了新的理解。

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.