Epigenomic mechanisms of risk and resilience: The role of parenting

风险和复原力的表观基因组机制：养育的作用

• 批准号: 10557910
• 负责人: Justin Parent
• 金额: $ 8.73万
• 依托单位: EMMA PENDLETON BRADLEY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557910
• 关键词: Acceleration; Accounting; Aftercare; Age; Aging; Attenuated; Behavioral; Bioinformatics; Biological; Biological Markers; Buffers; Child; Child Behavior; Child Rearing; Chronic Disease; Clinical; Clinical Trials; DNA Methylation; Data; Development; Developmental Delay Disorders; Disparity; Early Intervention; Educational Intervention; Environmental Impact; Epigenetic Process; Exposure to; Foundations; Funding; Future; Genes; Glucocorticoids; Hispanic; Home; Human; Inflammatory; Inflammatory Response; Informal Social Control; Interdisciplinary Study; Intervention; Knowledge; Latinx; Life; Literature; Maintenance; Measures; Methods; Molecular Biology; Neurosecretory Systems; Not Hispanic or Latino; Outcome; Parents; Pathway Analysis; Pathway interactions; Pattern; Poverty; Prevention; Prevention approach; Prevention program; Process; Psychopathology; Public Health; Randomized; Randomized, Controlled Trials; Reduce health disparities; Research; Risk; Role; Scientist; Signal Transduction; Signaling Protein; Site; Social Change; Social Environment; Standardization; Stress; Time; Training Programs; Trauma; United States National Institutes of Health; Work; Youth; behavioral outcome; biological adaptation to stress; biological systems; biosignature; design; disadvantaged background; early detection biomarkers; early experience; early life adversity; economic disparity; epigenome; epigenome-wide association studies; epigenomics; evidence base; follow-up; group intervention; high risk; improved; individualized prevention; informant; innovation; intervention program; methylomics; mood regulation; parental role; personalized care; personalized intervention; personalized medicine; precision medicine; prevent; preventive intervention; promote resilience; protective factors; public health relevance; resilience; response; response biomarker; service intervention; social; stressor; treatment response

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.

项目摘要 西班牙裔青年有发展，行为或社会的高风险的三倍 与白人非西班牙裔儿童相比，延误。导致这种风险差异是不成比例的 西班牙裔儿童生活在贫困中，增加了暴露于早期生活逆境的风险 这给心理病理学发展和慢性疾病的终生风险带来了重大风险。 早期逆境的不成比例经历可能会影响风险的关键过程 后来的心理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 神经内分泌和炎症反应涉及压力反应的基因的变化。尽管 对风险过程的社会表观基因组研究的承诺和进展，现存的重大局限 文献是对如何预防或反转逆境的生物嵌入的基本理解 尚未实现，几乎没有了解影响这些发展的保护因素的作用 轨迹。实际上，先前在人类的工作几乎完全是横截面的，专注于 不利的环境影响，极大地限制了我们对表观基因组过程的理解 及其对干预措施的积极延展性。拟议的研究将利用正在进行的NIH资助的R01 （＃HD084497）通过对家庭行为父母培训的随机对照试验进行评估 干预，改变社会环境（即育儿功能失调）如何改变处于危险中的表观基因组 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。在当前的建议中，我们建议使用 平衡分析方法，包括（1）对参与基因的假设驱动的途径分析 神经内分泌和对压力的炎症反应，（2）以前拉动位点的目标设计 在驱动的EWAS研究中鉴定出来创建多面性风险评分，（3）无假设 全基因组整个协会研究。除了检查儿童DNA甲基化变化的轨迹外， 我们将确定暴露于保护因素（积极育儿）是否缓解逆境对 在敏感的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 基于儿童和母体DNA甲基化的生物签名对早期干预的反应。对于所有目标， 我们将使用多种信息，多方法设计，其中包括对育儿的观察，基于任务 儿童自我调节的措施，对儿童发育和临床结果的标准化评估， 独立的临床评估符，以及儿童和母体DNA甲基化。这项研究将促进 通过识别早期的表观基因组生物标志物的应用精确医学和预防方法 干预响应模式将允许在风险识别和个性化的风险识别中实现创新策略 预防，共同对减少健康差异的有效方法有了新的了解。