Mechanisms of resilience to developmental stress in children and adolescents.

项目摘要/摘要 儿童和青少年在成长过程中往往面临着巨大的发展压力(即创伤)。而对于 一些，这将发展轨迹转移到精神和一般健康障碍，另一些是 适应力强。大多数发展精神病理学的研究都集中在风险上，而对风险的了解很少。 赋予韧性的机制。目前的研究旨在确定生物学(基因组，免疫)， 心理和认知机制支撑着年轻人的韧性，定义为情绪低落- 有大量发展应激暴露(即创伤和家庭)的青少年的焦虑和自杀结果 抑郁症病史)。阐明弹性机制具有巨大的临床意义，因为它将改善 对患抑郁症和/或自杀行为的风险进行分层，并可确定生物、心理 和认知目标，这些目标可以为今后的预防干预提供信息，旨在促进 复原力，减少与童年逆境有关的心理和一般健康不良后果。这个 这项研究利用了费城神经发育队列中的大量年轻人的基因分型数据 (PNC)，已经在认知表现和精神病理学方面进行了全面的表型分析，并且 据报道有大量创伤暴露。这项拟议的研究将基因组和认知数据与 在对约9500名PNC青年的横断面分析中用于确定复原力的临床措施(目标1)； 整合了抑郁症和自杀措施的纵向数据，从电子医疗记录中提取 约750名PNC青年的子集(目标2)；并依赖于包括免疫档案在内的前瞻性数据收集 选定的PNC个人，以识别复原力的免疫签名(目标3)。集成 具有临床、认知和免疫数据的基因组将支持预测性建模和大数据驱动的分析 将允许确定复原力机制。候选人是一名儿童和青少年精神病学家 内科科学家，致力于对有精神疾病风险的青少年进行翻译研究。他的 职业生涯的首要目标是开发早期识别亚临床表型的方法 出现严重精神障碍(即抑郁症和自杀未遂)，并通过神经科学了解 通过采取干预措施，将发展轨迹从风险轨迹转向韧性轨迹。职业生涯发展 Plans利用了一支多学科的指导团队。它包括与小学一对一的指导 临床研究导师以及基因组、生物统计学、神经认知和免疫系统专家 导师，在数据收集和统计分析方面与实践研究监督相结合，并进行授课 课程作业和工作坊。该计划是为满足研究和培训目标而定制的。该项目将是 在费城儿童医院和费城大学的培养环境中进行 这将提供学术指导和执行研究所需的资源 和培训目标，使候选人能够开始独立的研究生涯。

PROJECT SUMMARY/ ABSTRACT Children and adolescents often grow up in the face of substantial developmental stress (i.e. trauma). While for some, this shifts the developmental trajectory to that of mental and general health disorders, others are resilient. Most research on developmental psychopathology is focused on risk while little is known on the mechanisms that confer resilience. The current study aims to identify biological (genomic, immune), psychological and cognitive mechanisms that underpin resilience in youth as defined by having low mood- anxiety and suicidal outcomes in youth with substantial developmental stress exposure (i.e. trauma and family history of depression). Elucidating resilience mechanisms has huge clinical implications as it will improve stratification of risk to develop depression and/or suicidal behavior, and could identify biological, psychological and cognitive targets that can inform development of future preventive interventions aimed at promoting resilience, reducing the mental and general health adverse outcomes associated with childhood adversity. The study capitalizes on a large dataset of genotyped youths from the Philadelphia Neurodevelopmental Cohort (PNC), that have been comprehensively phenotyped for cognitive performance and psychopathology, and that reported substantial trauma exposure. The proposed research integrates genomic and cognitive data with clinical measures used to define resilience in cross sectional analysis of ~9500 PNC youths (Aim 1); incorporates longitudinal data of depression and suicide measures, pulled from electronic medical record in a subset of ~750 PNC youths (Aim 2); and relies on prospective data collection that includes immune profiling of selected PNC individuals to allow identification of immune signature of resilience (Aim 3). Integration of genomic with clinical, cognitive and immune data will allow predictive modeling, and Big Data driven analysis will allow identification of resilience mechanisms. The candidate is a Child and Adolescent Psychiatrist physician scientist who is committed to translational research in youth at risk for psychiatric conditions. His overarching career goal is to develop methods for early identification of subclinical phenotypes before the onset of major psychiatric disorders (i.e. depression and suicide attempts) and, through neuroscience informed interventions, divert the developmental trajectory from that of risk to that of resilience. The career development plan capitalizes on a multidisciplinary mentorship team. It involves one-on one mentoring with the primary “clinical research” mentor as well as the genomic, biostatistical, neurocognitive and immune system expert co- mentors, integrated with hands on research supervision in data collection and statistical analysis, and didactic coursework and workshops. The program is tailored to meet research and training aims. The project will be conducted in the fostering environment of the Children’s Hospital of Philadelphia and the University of Pennsylvania, that will provide the academic mentorship and the required resources to execute the research and training aims, allowing the candidate to launch an independent research career.