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.

项目概要 西班牙裔青少年在发育、行为或社交方面面临高风险的可能性是其近三倍 与非西班牙裔白人儿童相比，延迟。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以及面临早年环境逆境的风险增加，所有这些 这给精神病理学的发展带来了巨大的风险，并带来了患慢性病的终生风险。 早期逆境的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将逆境暴露的生物嵌入 涉及神经内分泌和应激反应炎症反应的基因发生变化。尽管 风险过程社会表观基因组研究的前景和进展，这是现有研究的一个重大限制 文献是对如何预防或逆转逆境的生物嵌入的基本理解 尚未实现，对影响这些发育的保护因素的作用知之甚少 轨迹。事实上，之前对人类的研究几乎都是横断面的，并且集中于 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 及其对干预措施的积极可塑性。拟议的研究将利用 NIH 资助的正在进行的 R01 （#HD084497）通过家庭行为家长培训的随机对照试验进行评估 干预，改变社会环境（即功能失调的养育方式）如何改变高危人群的表观基因组 西班牙裔学龄前儿童有可能建立一个促进弹性和适应能力的生物基础 潜在地改善逆境的生物嵌入。在当前的提案中，我们建议使用 平衡分析方法，包括（1）对参与的基因进行假设驱动的途径分析 神经内分泌和炎症对压力的反应，（2）一种有针对性的设计，可以拉动先前的位点 在强有力的 EWAS 研究中确定，以创建多表观遗传风险评分，以及 (3) 无假设 全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， 我们将确定暴露于保护性因素（积极养育）是否可以缓冲逆境对孩子的影响 敏感发育阶段加速衰老的生物标志物。最后，我们将探讨表观基因组学 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、多方法的设计，包括对育儿的观察、基于任务的 儿童自我调节措施、儿童发育和临床结果的标准化评估、 独立的临床评估者，以及儿童和父母的 DNA 甲基化。这项研究将有助于 通过识别早期疾病的表观基因组生物标志物来应用精准医学和预防方法 干预响应模式将允许风险识别和个性化方面的创新策略 预防，共同导致对减少健康差距的有效方法有了新的认识。