Epigenetic Investigation of Trauma in PTSD and Depression

 描述(申请人提供)：这项建议旨在培训医学博士临床研究人员在新的领域：1)创伤后应激障碍(PTSD)和严重抑郁障碍(MDD)的表观遗传学；以及2)用于全基因组数据分析的生物信息学。这项培训将通过一个项目完成，该项目将利用已经确定的1300名女性军事人员的独特核心，这些人员具有全面的创伤病史和精神健康诊断和治疗基线数据。目标将是确定创伤、创伤后应激障碍和MDD易感性的表观遗传生物标记物。不幸的是，女性军人在服役期间遭受性创伤的风险很高，高达30%的人患有这种经历。在这些女性中，超过25%的人患有创伤后应激障碍，超过14%的人患有MDD。虽然遗传易感性在这些疾病的发展中发挥了作用，但创伤暴露引起的表观遗传修饰可能在疾病易感性中起着关键作用。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，但需要极大的统计和生物信息学复杂性才能确定其中哪些在疾病中起到病因学作用。申请人建议学习处理全基因组DNA甲基化数据的关键技术。这将在一定程度上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的精神病学表观遗传学培训，这位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完成：1)确定特定基因中的DNA甲基化(DNaM)水平是否与女性在军队中遭受性侵犯(SAIM)的历史相关；2)确定特定基因中的dNaM水平是否与暴露于SAIM的情况下患创伤后应激障碍和MDD的可能性相关；以及3)在这一探索性目标中，确定特定基因内的dNaM水平是否与暴露于SAIM的PTSD和MDD患者的治疗反应可能性相关。这项建议将使申请者成为将生物信息学和表观遗传学结合在一起研究创伤后应激障碍和MDD的专家。结果将提供对生物标志物的新见解，这些生物标志物可能对评估创伤后应激障碍和MDD的高危人群有价值，并可能在确定哪些人应该开始预防性干预方面有价值。此外，这项培训将为申请者提供一套广泛适用于复杂精神疾病表观遗传标记研究的工具。

 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.