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

描述(由申请者提供)：这个有指导的研究科学家职业发展奖(K01)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，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，如抑郁和焦虑，具有复杂的病因，并通过基因、经验及其相互作用(例如，基因-环境相互作用；GxE)的影响而出现，但确定GxE相互作用的努力取得了好坏参半的结果。目前建议的总体目标是检验这样一种假设，即GxE效应在发育的“敏感期”最强，也就是发育中的人脑对经历特别脆弱或敏感的一段时间窗口，包括暴露在社会逆境中(例如，虐待儿童、社会剥夺)。这一主要假设将在三个目标上得到检验。目标1将考察暴露在逆境中的时机对情绪识别技能和随后内化症状发展的影响。目的2研究“敏感期相关基因通路”的遗传变异对情绪识别技能和内化症状的影响。与敏感期相关的基因通路将由两组基因定义。第一组基因将在NIMH资助的脑云资源中确定，这是一个人类前额皮质基因表达的时间模式数据库。在这个基因集中选择的基因将在生命的早期高度和差异地表达。第二个基因集将是动物研究中显示的调节敏感期(即GAD2、OTX2、rtnf、lynx1和BDNF)时间的基因的人类同源基因。SNP将被映射到 基因使用ProxyGeneLD。将同时模拟通路中的所有SNP；因此不会进行SNP水平的测试。目的3研究基因与逆境相互作用(GxE)，重点研究敏感期相关基因通路的遗传变异是否改变逆境时机与情绪识别和内化症状之间的关联。拟议的研究结果有助于确定在生命周期中，干预措施在预防内化性症状方面最有效的时期，逆境增加精神病理学风险的机制，以及治疗内化性症状和障碍的可能目标。拟议奖项的培训部分集中在马萨诸塞州综合医院的精神病学和神经发育遗传学部门，旨在为应聘者提供实现其职业目标和完成K01研究目标所需的技能和知识。候选人艾琳·C·邓恩博士有社会和精神流行病学的背景，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暴露在逆境中与随后的症状内化风险联系起来的机制方面的培训。她的长期职业目标是成为一名独立的、翻译的流行病学家，拥有翻译基础科学研究成果并改善人口健康水平的技能和知识。为了实现这一目标，邓恩博士将接受两个新领域的培训：(1)流行病学的基因组和生物信息学工具；(2)精神病理学的发展神经科学。在这些培训领域内，邓恩博士将发展利用生物信息学资源、进行路径和基因集分析以及识别基因表达模式的技能。这些新获得的技能将与概念和方法战略相结合，以确定发展中的敏感期，以及暴露在逆境中增加精神病理学风险的途径。培训活动包括课程作业、讲习班、出席会议以及受监督的研究项目、个人培训以及持续的监督和咨询。培训将由两名国际公认的导师(乔丹·斯莫勒博士和查尔斯·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咨询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和精神障碍方面的专家组成。培训目标将应用于该奖项的研究部分。研究部分由Dunn博士、Smoller博士和Nelson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最大的两个单独基因分型的普通人群数据集的数据，在这些数据集中，内化症状、情绪调节技能和暴露在逆境中的表现从童年早期到青春期都有很深的表型。这些研究是：雅芳父母和孩子纵向研究(n=13,988)和R世代研究(n=9,745)。总而言之，这些培训和研究项目将构成邓恩博士将在颁奖期第三年准备的R01提案的基础。R01将采用在授奖期间完成的培训和研究，并将寻求复制和扩展支持GxE知情模型的结果，以确定敏感期。根据K01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。它还可包括减轻或扭转敏感期内暴露于逆境的影响的其他因素(例如，胎儿药物暴露)。

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).