Biological, Behavioral, and Genetic Mechanisms in the Intergenerational Transmission of Toxic Stress

项目摘要/摘要： 这个独立之路奖的目的是为申请者准备一个独立的，持续的 结合生物学、行为学和遗传学的概念和方法来理解的研究计划 并防止易受伤害的儿童和家庭出现中毒压力。毒性应激描述的是持续升高的 下丘脑-垂体-肾上腺(HPA)轴是对童年逆境的反应(例如，贫穷， 虐待，父母精神疾病)，可以通过支持性照顾来缓冲，并导致健康状况不佳和 在整个生命周期内的发展。有毒压力也可以代代相传，但潜在的 人们对其传播机制知之甚少。这项研究的基础是美国国立卫生研究院-- 申请者资助的博士前研究(F31NR016385)，其中 母亲的儿童史(逆境和家庭力量)、目前的照看(照看反应和 父母压力)和儿童毒性应激指标(生物、健康、行为)在 多民族、低收入的母子二人组。基于持续睡眠和昼夜节律的重要性 健康的下丘脑轴功能的节律模式，在K99阶段，申请者将检查 使用母子二重肌动描记数据来衡量一致的日常生活(例如，规律的就寝时间、体力活动 活动)，并检验这样一种假设，即照顾者可以通过每天提供 常规的连贯性。K99阶段将包括有关睡眠/昼夜节律的概念和方法的培训 节奏和基因-环境(GxE)的相互作用，因为已知个体对 儿童早期经历的影响。该培训将由专家指导和量身定做 培训经验，包括课程作业、定向阅读、研讨会和科学会议。通知人 在研究的F31和K99阶段检测到的关系，在R00阶段，候选人将检查 产妇儿童史、当前产妇照料(一致的日常生活方式、 照看反应性、父母压力)和儿童毒性压力指标 多民族、低收入母子二人组(3-4岁儿童)。毒性应激的指标包括 应聘者有过往专长的生物标志物(如毛发皮质醇、唾液细胞因子)。这个 候选人还将探索候选基因中与照顾有关的基因变异的程度 (OXTR，DRD4)和应激(BDNF，IL-6，FTO)导致母亲和儿童对这些影响的易感性 关于童年早期经历的。这项研究的结果将被应聘者用来进一步检查 代际传递毒害应激和保护因素，最终养成精准健康 基于家庭生物行为、遗传和环境的旨在预防中毒应激的干预措施 特点。

PROJECT SUMMARY/ABSTRACT: The purpose of this Pathway to Independence Award is to prepare the applicant for an independent, sustained program of research that incorporates biological, behavioral, and genetic concepts and methods to understand and prevent toxic stress among vulnerable children and families. Toxic stress describes persistent elevation of the hypothalamic-pituitary-adrenal (HPA) axis that occurs in response to childhood adversity (e.g. poverty, maltreatment, parental mental illness), can be buffered by supportive caregiving, and leads to poor health and development across the lifespan. Toxic stress can also be transmitted through generations, but the underlying mechanisms of transmission are poorly understood. The research conducted in this study builds on NIH- funded predoctoral research conducted by the applicant (F31NR016385), in which novel relationships between mothers' childhood history (adversity and family strengths), current caregiving (caregiving responsiveness and parental stress), and child indicators of toxic stress (biological, health, behavioral) were detected among multiethnic, low-income maternal-child-dyads. Based on the importance of consistent sleep and circadian rhythm patterns for healthy HPA-axis functioning, in the K99 phase the applicant will examine the feasibility of using mother-child dyad actigraphy data to measure consistent daily routines (e.g. regular bedtimes, physical activity) and test the hypothesis that caregivers can protect their children from toxic stress by providing daily routine consistency. The K99 phase will include training in concepts and methods related to sleep/circadian rhythm and gene-environment (GxE) interactions, as individuals are known to be differentially susceptible to the effects of early childhood experiences. This training will be supported by expert mentorship and tailored training experiences including coursework, directed readings, seminars, and scientific meetings. Informed by relationships detected in the F31 and K99 phases of the study, in the R00 phase the candidate will examine relationships among maternal childhood history, current maternal caregiving (consistent daily routines, caregiving responsiveness, parental stress) and child indicators of toxic stress in a fully-powered sample of multiethnic, low-income mother-child dyads (children age 3-4 years). Indicators of toxic stress will include biological markers (e.g. hair cortisol, salivary cytokines) with which the candidate has prior expertise. The candidate will also explore the extent to which genotypic variation in candidate genes related to caregiving (OXTR, DRD4) and stress (BDNF, IL-6, FTO) contribute to mothers' and children's susceptibility to the effects of early childhood experiences. The results of this study will be used by the candidate to further examine intergenerational transmission of toxic stress and protective factors, and ultimately develop a precision health intervention that aims to prevent toxic stress based on families' biobehavioral, genetic and environmental characteristics.