Genes, early adversity, and sensitive periods in social-emotional development

基因、早期逆境和社会情感发展的敏感期

• 批准号: 8765685
• 负责人: Erin Cathleen Dunn
• 金额: $ 18.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765685
• 关键词: Adolescence; Adolescent; Age; Animals; Anxiety; Area; Award; Basic Science; Bioinformatics; Birth; Brain; Brain-Derived Neurotrophic Factor; Child; Child Abuse; Child Abuse and Neglect; Cognitive; Complex; Consultations; Data; Data Set; Databases; Development; Disease; Educational workshop; Emotional; Emotions; Environmental Exposure; Epidemiologic Methods; Epidemiologist; Epidemiology; Etiology; Exposure to; Funding; Gene Expression; Gene Expression Profile; General Hospitals; General Population; Generations; Genes; Genetic; Genetic Models; Genetic Variation; Genomics; Genotype; Goals; Grant; Health; Health Resources; Health Status; Human; Human Development; Individual; Intervention; Investments; Jordan; K-Series Research Career Programs; Knock-in Mouse; Knowledge; Life; Link; Literature; Live Birth; Longevity; Longitudinal Studies; Maps; Massachusetts; Measures; Mediating; Mental Depression; Mental disorders; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Molecular; National Institute of Mental Health; Neurosciences; Outcome; Parents; Pathway interactions; Phenotype; Population; Prefrontal Cortex; Process; Psychopathology; Public Health; Relative Risks; Research; Research Design; Research Domain Criteria; Research Project Grants; Research Training; Resources; Risk; Sample Size; Scientist; Sensory; Strategic Planning; Supervision; Symptoms; System; Testing; Time; Training; Training Activity; Training Programs; Translating; Translational Research; Variant; Visual; Visual system structure; Work; Youth; base; career; cohort; design; early childhood; emotion regulation; experience; fetal drug exposure; gene environment interaction; genome-wide; improved; neurobehavioral; novel; prevent; programs; sensory system; skills; social; social deprivation; social skills; success; symposium; tool; training project

DESCRIPTION (provided by applicant): This Mentored Research Scientist Career Development Award (K01) will provide the candidate with the necessary skills and knowledge to develop an independent program of research that uses epidemiological methods to identify genetic and environmental determinants of psychiatric disorders. Although psychiatric symptoms and disorders, such as depression and anxiety, have a complex etiology and emerge through the effect of genes, experience, and their interaction (e.g., gene-environment interaction; GxE), efforts to identify GxE interactions have had mixed success. The overall aim of the current proposal is to test the hypothesis that GxE effects are strongest during "sensitive periods" in development, or windows of time in the lifespan when the developing human brain is particularly vulnerable or sensitive to experience, including exposure to social adversity (e.g., child maltreatment, social deprivation). This main hypothesis will be tested in three aims. Aim 1 will examine the effect of timing of exposure to adversity on emotion recognition skills and subsequent development of internalizing symptoms. Aim 2 will examine the effect of genetic variation in "sensitive period relevant gene pathways" on emotion recognition skills and internalizing symptoms. Sensitive period relevant gene pathways will be defined by two sets of genes. The first will be sets of genes identified in the NIMH-funded Brain Cloud resource, a database of temporal patterns of gene expression in the human prefrontal cortex. Genes selected in this gene set will be highly and differentially expressed in the early years of life. Te second gene set will be the human orthologues of genes shown in animal studies to regulate the timing of sensitive periods (i.e., gad2, otx2, rtnf, lynx1, and bdnf). SNPs will be mapped to a gene using ProxyGeneLD. All SNPs in the pathway will be modeled simultaneously; thus no SNP-level tests will be conducted. Aim 3 will investigate gene-by adversity interactions (GxE), focusing on whether genetic variation in sensitive period relevant gene pathways modifies the association between timing of adversity and both emotion recognition and internalizing symptoms. Findings generated from the proposed research can help identify periods in the lifespan when interventions could be most effective in preventing internalizing symptoms, mechanisms by which adversity increases risk for psychopathology, and possible targets to treat internalizing symptoms and disorders. The training component of the proposed award, centered in the Psychiatric and Neurodevelopmental Genetics Unit at the Massachusetts General Hospital, is designed to provide the candidate with the skills and knowledge necessary to reach her career goals and complete the K01 research aims. The candidate, Dr. Erin C. Dunn, has a background in social and psychiatric epidemiology, but no training in the use of bioinformatics tools, large-scale genomic data, and mechanisms linking exposure to adversity to subsequent risk for internalizing symptoms. Her long-term career goal is to become an independent, translational epidemiologist, with the skills and knowledge to translate findings from basic science research and improve population-level health. To accomplish this goal, Dr. Dunn will be trained in two novel areas: (1) genomic and bioinformatics tools for epidemiology; and (2) developmental neuroscience of psychopathology. Within these training areas, Dr. Dunn will develop the skills to use bioinformatics resources, conduct pathway and gene set analyses, and identify patterns of gene expression. These newly-acquired skills will be integrated with conceptual and methodological strategies to identify sensitive periods in development and the pathways through which exposure to adversity increases risk for psychopathology. Training activities include coursework, workshops, conference attendance, as well as supervised research projects, individual training, and ongoing supervision and consultation. Training will be overseen by two internationally recognized mentors (Dr. Jordan Smoller and Dr. Charles Nelson) and a panel of expert consultants. This interdisciplinary mentorship and consultant team is comprised of experts in molecular and statistical genetics, gene expression, bioinformatics, developmental neuroscience, GxE, and psychiatric disorders. The training aims will be applied in the research component of the award. The research component consists of two studies designed by Drs. Dunn, Smoller, and Nelson to test the hypotheses linked to the aims noted above. The studies use data from the two largest, individually- genotyped general population datasets in the world, in which internalizing symptoms, emotion regulation skills, and exposure to adversity have been deeply phenotyped from early childhood through adolescence. These studies are: the Avon Longitudinal Study of Parents and Children (n=13,988) and the Generation R study (n=9,745). Together, these training and research projects will constitute the basis for an R01 proposal that Dr. Dunn will prepare in the third year of the award period. This R01 will employ the training and research completed during the award period and will seek to replicate and extend findings that support a GxE informed model to identify sensitive periods. Depending on the K01 results, such a model could include specific gene sets, measures of emotion recognition skills and other social competencies, timing of adversity, and measures of depression, anxiety, and internalizing symptoms. It could also include other factors that mitigate or reverse the effects of exposure to adversity during the sensitive period (e.g., fetal drug exposure).

该指导研究科学家职业发展奖（K 01）将为候选人提供必要的技能和知识，以开发一个独立的研究计划，该计划使用流行病学方法来确定精神疾病的遗传和环境决定因素。虽然精神症状和障碍，如抑郁症和焦虑症，有一个复杂的病因，并通过基因，经验和它们的相互作用（例如，基因-环境相互作用; GxE），鉴定GxE相互作用的努力取得了混合的成功。当前提案的总体目标是检验GxE效应在发育的“敏感期”或生命周期中的时间窗口期间最强的假设，此时发育中的人类大脑对经验特别脆弱或敏感，包括暴露于社会逆境（例如，儿童虐待、社会剥夺）。这一主要假设将在三个目标中得到检验。目的1将研究暴露于逆境的时间对情绪识别技能和随后的内化症状的发展的影响。目的二将探讨“敏感期相关基因路径”的基因变异对情绪辨识技巧与内化症状的影响。敏感期相关基因通路将由两组基因定义。第一个将是在NIMH资助的Brain Cloud资源中识别的基因集，Brain Cloud资源是人类前额叶皮层基因表达时间模式的数据库。在该基因集中选择的基因将在生命的早期高度和差异表达。第二个基因集将是动物研究中显示的基因的人类直向同源物，以调节敏感期的时间（即，GAD 2、OTX 2、RTNF、Lynx 1和BDNF）。SNP将被映射到 使用ProxyGeneLD的基因。将同时对途径中的所有SNP进行建模;因此将不进行SNP水平测试。目的3将研究基因与逆境的相互作用（GxE），重点是敏感期相关基因通路的遗传变异是否会改变逆境发生的时间与情绪识别和内化症状之间的关联。从拟议的研究中产生的结果可以帮助确定干预措施在预防内化症状方面最有效的生命周期，逆境增加精神病理学风险的机制，以及治疗内化症状和障碍的可能目标。该奖项的培训部分集中在马萨诸塞州总医院的精神病学和神经发育遗传学部门，旨在为候选人提供实现其职业目标和完成K 01研究目标所需的技能和知识。候选人艾琳·C博士邓恩有社会和精神病学的背景，但没有接受过使用生物信息学工具、大规模基因组数据以及将逆境暴露与随后的内化症状风险联系起来的机制的培训。她的长期职业目标是成为一名独立的翻译流行病学家，拥有翻译基础科学研究结果和改善人口健康水平的技能和知识。为了实现这一目标，邓恩博士将在两个新领域接受培训：（1）流行病学的基因组和生物信息学工具;（2）精神病理学的发育神经科学。在这些培训领域内，邓恩博士将发展使用生物信息学资源的技能，进行途径和基因集分析，并确定基因表达模式。这些新获得的技能将与概念和方法策略相结合，以确定发展中的敏感时期以及暴露于逆境增加精神病理学风险的途径。培训活动包括课程、讲习班、出席会议以及监督研究项目、个人培训和持续监督和咨询。培训将由两名国际公认的导师（Jordan Smoller博士和Charles纳尔逊博士）和一个专家顾问小组监督。这个跨学科的指导和顾问团队由分子和统计遗传学，基因表达，生物信息学，发育神经科学，GxE和精神疾病的专家组成。培训目标将应用于该奖项的研究部分。研究部分由Dunn、Smoller和纳尔逊博士设计的两项研究组成，以检验与上述目标相关的假设。这些研究使用了来自世界上两个最大的、单独基因分型的一般人群数据集的数据，其中内化症状、情绪调节技能和逆境暴露从幼儿期到青春期都进行了深入的表型分析。这些研究是：雅芳父母和子女纵向研究（n= 13，988）和R世代研究（n= 9，745）。这些培训和研究项目将共同构成邓恩博士将在奖励期第三年准备的R 01提案的基础。该R 01将采用在授予期间完成的培训和研究，并将寻求复制和扩展支持GxE知情模型的发现，以确定敏感期。根据K 01的结果，这样的模型可能包括特定的基因组，情绪识别技能和其他社交能力的测量，逆境的时间，以及抑郁，焦虑和内化症状的测量。它还可以包括在敏感时期减轻或扭转逆境影响的其他因素（例如，胎儿药物暴露）。