Epigenetic Response to Early Life Stress and the Impact on Cardiovascular Health

描述（由申请人提供）：儿童期逆境，以虐待，忽视和家庭功能障碍为特征，是一个对个人，家庭和社会产生巨大影响的国家问题，对公共卫生具有重要意义。越来越多的证据 研究表明，童年时期的创伤经历与成年后的健康下降有关，包括药物滥用、精神障碍和心血管疾病。然而，潜在的生物学机制仍不清楚。表观遗传学，包括DNA甲基化，在基因调控中起着重要作用，以响应外部环境信号。这种机制与行为生物学特别相关。最近的研究和我们的初步结果发现，表观遗传学（例如DNA甲基化）参与塑造对生命早期社会环境的内分泌和免疫反应。因此，我们提出，暴露于早期生活压力（ELS）可能会改变DNA甲基化模式，这些修饰随着时间的推移而持续存在，导致日后患心血管疾病的风险增加。自1989年以来，我们建立了一个纵向队列，其中600多名儿童在22年内接受了16次随访。在这些参与者中评估了18岁之前的不良童年经历（ACE），包括童年虐待（例如性虐待），忽视（例如情感虐待）和家庭功能障碍（例如家庭成员中的药物滥用或家庭暴力）。严重暴露于ACE的儿童，即在儿童时期经历多起事件（e4）的儿童，在成年早期出现了可检测到的精神问题和不利的血管和心脏功能。通过利用这一成熟的纵向队列，我们的目标是确定ELS相关的DNA甲基化修饰在早期的年轻成年人，并检查他们对心血管健康的影响随着时间的推移。本项目的具体目标是：（1）通过全基因组筛查、交叉访问验证和功能检测三步方法确定与ELS相关的DNA甲基化修饰;（2）研究ACE暴露对DNA甲基化水平的纵向变化，并测试年轻人的高危行为和低社会经济地位是否会加速这一过程;（3）检查ELS相关甲基化修饰随时间对多种心血管测量的发展的纵向贡献。该项目将为研究DNA甲基化在具有童年逆境史的个体中赋予心血管健康风险的作用奠定基础，并确定新的病因学，表明早期生活心理压力如何“生物嵌入”并影响整个生命过程的健康结果，这可能有助于开发新的预防和干预策略，以减少与压力相关的健康问题相关的负担。

DESCRIPTION (provided by applicant): Childhood adversity, characterized by abuse, neglect and household dysfunction, is a national problem that exerts an enormous impact on individuals, families and society, and is of great significance for public health. Growing evidence suggests that traumatic experiences in childhood are associated with health decline in adulthood, including substance abuse, mental disorders and cardiovascular disease. However, the underlying biological mechanisms remain unclear. Epigenetics, including DNA methylation, plays an important role in gene regulation in response to external environmental signals. This mechanism is of particular relevance for behavioral biology. Recent studies and our preliminary results have found that epigenetics, e.g. DNA methylation, is involved in shaping the endocrine and immune responses to early life social environment. Therefore, we propose that exposure to early life stress (ELS) may modify DNA methylation patterns and these modification are persistent over time leading to increased risk for cardiovascular disease later in life. Since 1989 we have established a longitudinal cohort in which over 600 children have been followed-up 16 times in 22 years. Adverse childhood experiences (ACEs) prior to age 18 has been assessed in these participants, including childhood abuse (e.g. sexual), neglect (e.g. emotional), and growing up with household dysfunction (e.g. substance abuse or domestic violence in family members). Children who were severely exposed to ACEs, i.e. experienced multiple events (e4) during childhood, have developed mental problem and unfavorable vascular and cardiac function detectable in early adulthood. By taking advantage of this well-established longitudinal cohort, we aim to identify ELS-related DNA methylation modifications in early young adulthood and to examine their impacts on cardiovascular health over time. The specific aims of this project are: (1)To identify ELS-related DNA methylation modifications in a 3-step approach: genome-wide screening, cross-visit validating and functional testing; (2) To examine the longitudinal varies of DNA methylation levels in response to ACE exposures and to test whether at-risk behaviors and low socioeconomic status in young adulthood can accelerate this process; (3) To examine the longitudinal contributions of ELS-related methylation modifications to the development of multiple cardiovascular measures over time. This project will lay the groundwork for examining the role of DNA methylation in conferring risk for cardiovascular health in individuals with history of childhood adversity, and identify new etiology indicating how early lif psychological stress becomes "biologically embedded" and influences health outcomes through the life course, which may aid in developing novel prevention and intervention strategies to reduce the burden associated with stress-related health problems.