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

项目总结/摘要： 这个独立之路奖的目的是准备申请人的独立，持续 一个研究计划，结合生物学，行为学和遗传学的概念和方法，以了解 并防止弱势儿童和家庭的有毒压力。中毒性应激是指 下丘脑-垂体-肾上腺（HPA）轴是对童年逆境（例如贫穷， 虐待，父母的精神疾病），可以通过支持性的照顾来缓冲，并导致健康状况不佳， 整个生命周期的发展。有毒的压力也可以通过几代人，但潜在的 传播机制知之甚少。这项研究的基础是NIH- 申请人资助的博士前研究（F31 NR 016385），其中， 母亲的童年历史（逆境和家庭优势），目前的成长（成长反应和 父母压力）和儿童毒性压力指标（生物，健康，行为）被检测到， 多种族低收入的母子组合基于持续睡眠和昼夜节律的重要性 健康HPA轴功能的节律模式，在K99阶段，申请人将检查 使用母亲-孩子的双动记录数据来测量一致的日常生活（例如，规律的就寝时间、身体状况）。 活动），并检验这一假设，即照顾者可以保护他们的孩子免受有毒压力， 常规一致性。K99阶段将包括与睡眠/昼夜节律相关的概念和方法的培训 节律和基因-环境（GxE）相互作用，因为已知个体对 早期童年经历的影响。这一培训将得到专家指导的支持， 培训经历包括课程作业、指导性阅读、研讨会和科学会议。通知 在研究的F31和K99阶段检测到的关系，在R 00阶段，候选人将检查 母亲童年史，目前母亲的生活方式（一致的日常生活， 在一个完全有效的样本中， 多族裔、低收入的母子二人组（3-4岁儿童）。毒性压力的指标将包括 候选人具有先前专业知识的生物标志物（例如毛发皮质醇、唾液细胞因子）。的 候选人还将探索候选基因的基因型变异在多大程度上与遗传相关。 (OXTR DRD 4）和应激（BDNF，IL-6，FTO）有助于母亲和儿童对效应的易感性 of early早期childhood童年experiences经验.这项研究的结果将用于候选人进一步审查 有毒应激和保护因子的代际传递，最终养成精准健康 干预，旨在防止基于家庭的生物行为，遗传和环境的有毒压力 特色

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.