Epigenetic Investigation of Trauma in PTSD and Depression

 描述（由申请人提供）：本提案旨在培养医学博士。临床研究人员在新的领域：1）创伤后应激障碍（PTSD）和重性抑郁症（MDD）的表观遗传学; 2）生物信息学的基因组范围的数据分析。这一培训将通过一个项目来完成，该项目将利用一个已经确定的由1 300多名女性军事人员组成的独特小组，这些人员具有全面的创伤史和心理健康诊断和治疗基线数据。目标是确定创伤和PTSD和MDD易感性的表观遗传生物标志物。不幸的是，女性军人在服役期间遭受性创伤的风险很高，多达30%的人遭受过这种经历。在这些女性中，超过25%的人患上PTSD，超过14%的人患上MDD。虽然遗传易感性在这些疾病的发展中起作用，但创伤暴露诱导的表观遗传修饰可能在疾病易感性中起关键作用。随着下一代全基因组评估方法的出现，现在可以使用相对低成本、高通量的方法来研究DNA甲基化。虽然这些技术已经取得了巨大的飞跃，现在可以为我们提供大量的数据，但理解数据的方法仍在迎头赶上。虽然基于疾病的全基因组DNA甲基化测量可以在病例中发现数十万个表观遗传标记，但需要大量的统计和生物信息学复杂性来确定其中哪些在疾病中起病因作用。申请人提出学习处理全基因组DNA甲基化数据的关键技术。这将部分通过攻读生物信息学硕士学位来实现。他还将接受他的主要导师在精神病学表观遗传学方面的培训，他的导师是这一新领域的知名专家。该项目将通过以下具体目标来完成：1）确定特定基因内的DNA甲基化（DNAm）水平是否与女性在军队中暴露于性侵犯（SAIM）的历史相关; 2）确定特定基因内的DNAm水平是否与暴露于SAIM的PTSD和MDD的可能性相关;和3）在这个探索性目的中，确定特定基因内的DNAm水平是否与暴露于SAIM的PTSD和MDD中的治疗反应的可能性相关。该提案将允许申请人发展为PTSD和MDD研究中生物信息学和表观遗传学的专家。研究结果将为生物标志物提供新的见解，这些生物标志物可能在评估PTSD和MDD风险人群中具有价值，并可能在确定应启动预防性干预措施的人群中具有价值。此外，这项培训将为申请人提供一套工具，广泛适用于研究复杂精神疾病的表观遗传标记。

 DESCRIPTION (provided by applicant): This proposal aims at training an M.D. clinical researcher in the new areas of: 1) the epigenetics of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD); and 2) bioinformatics for genome- wide data analysis. This training will be accomplished through a project that will utilize an already identified unique cohot of >1,300 female military personnel with comprehensive trauma history and mental health diagnosis and treatment baseline data. The goal will be to identify epigenetic biomarkers of trauma and PTSD and MDD susceptibility. Unfortunately, female military personnel are at high risk for sexual trauma during their service, with up to 30% suffering from this experience. Among these women, over 25% develop PTSD and more than 14% develop MDD. While genetic susceptibility plays a role in the development of these disorders, epigenetic modifications induced by trauma exposure likely play a critical role in illness susceptibility. With the advent o next-generation genome-wide assessment approaches, relatively low-cost, high-throughput methods to study DNA methylation are now available. While these technologies have made enormous leaps forward and can now provide us with a torrent of data, the methods for making sense of the data are still catching up. While disease-based genome-wide DNA methylation measurement can turn up hundreds of thousands of epigenetic marks in cases, it takes great statistical and bioinformatic sophistication to determine which of them plays an etiologic role in illness. The applicant proposes to learn the critical techniques for handling genome- wide DNA methylation data. This will be accomplished in part through pursuit of a Master's degree in bioinformatics. He will also be trained in psychiatric epigenetics by his primary mentor, who is an established expert in this new field. This project will be accomplished through the following specific aims: 1) To determine whether DNA methylation (DNAm) levels within particular genes are correlated with a history of exposure to sexual assault in the military (SAIM) among women; 2) To determine whether DNAm levels within particular genes are correlated with the likelihood of developing PTSD and MDD, given exposure to SAIM; and 3) To determine, in this exploratory aim, whether DNAm levels within particular genes are correlated with the likelihood of treatment response in PTSD and MDD, given exposure to SAIM. This proposal will allow for the development of the applicant as an expert in bringing together bioinformatics and epigenetics in the study of PTSD and MDD. Results will provide new insights into biomarkers that could be of value in assessing people at risk for PTSD and MDD, and potentially in identifying those for whom preventive interventions should be initiated. In addition, this training will provide the applicant with a set of tools that will be widely applicable to the study of epigenetic marks acros complex psychiatric illnesses.