CAP - Genetic and Epigenetic Alterations as Biomarkers for PTSD Diagnosis

国家研究行动计划(NRAP)(2013)呼吁人们关注令人震惊的高水平 在服役人员和退伍军人中观察到与战斗有关的创伤后应激障碍的比率 支持伊拉克和阿富汗战争。因此，财团将缓解 创伤后应激障碍(CAP)的形成是为了a)显著推进创伤后应激障碍的治疗策略 包括对早期、慢性和潜伏性发病病例的干预措施，以及b)识别和 确认临床相关生物标志物为创伤后应激障碍的诊断和预后指标 以及共生疾病。该项目旨在通过以下方式填补NRAP中确定的空白 检查基于遗传的生物标记物识别创伤后应激障碍、创伤后应激障碍病程和 对创伤后应激障碍治疗的反应。我们计划利用现有的大量资源 强大的STAR存储库，用于检查一套全面的遗传和表观遗传学 与创伤后应激障碍相关的标记物。这些资源包括：(1)人力资源的集合 PTSD(n=30)和对照组(n=60)脑的死后组织；(2) 因创伤后应激障碍接受治疗的军人，在治疗前和6点采集血液 治疗后几个月(n=600)；和(3)对士兵的流行病学队列进行评估 部署前后支持持久自由行动，伊拉克自由 和新黎明，每个都包括血液采集和创伤后应激障碍评估 评估(n=4112)。使用全基因组微阵列和 测序方法，我们将：(1)识别遗传(SNP，mRNA)或表观遗传(DNA 甲基化，microRNA)创伤后应激障碍的改变；(2)表征神经元的形态 通过高尔基体染色观察创伤后应激障碍患者和对照组的特定脑区；(3) 在已识别的一组基因中确定顶级基因调控网络 用于指导生物标志物分析的样本；以及(4)系统地识别、验证和测试 基于RNA、SNPs、DNA甲基化和microRNA标记的生物标记 确定了基因。我们已经组建了一个合作的科学家团队，由一个 遗传流行病学家(威廉姆森博士)、精神病学遗传学家(格勒恩特博士)、 遗传学家(Carless博士)、神经解剖学家(Selemon博士)、人类尸检专家 (Young，Kleinman，Hyde，Thompson和Cruz博士)，生物统计学家(Mintz，Gelfond博士， 米凯莱克和杰菲)，以及临床心理学家(利茨博士)。此外，我们建议 与国防部集成系统生物学小组(Dr.Jett&Hammaieh)合作 利用SysBioCube从系统层面了解我们的“组学”数据 这将反过来指导我们的生物标记物发现工作。预计这个项目将是 填补创伤后应激障碍基因组和生物标记物空白的重要第一步 NRAP并促进诊断和预后生物标志物小组的开发 协助检测、治疗和预防创伤后应激障碍。

The National Research Action Plan (NRAP) (2013) called attention to the alarmingly high rates of combat-related PTSD observed among service members and veterans deployed in support of the wars in Iraq and Afghanistan. As a result, the Consortium to Alleviate PTSD (CAP) was formed to a) significantly advance treatment strategies for PTSD including interventions for early, chronic, and latent onset cases, and b) to identify and confirm clinically relevant biomarkers as diagnostic and prognostic indicators of PTSD and co-occurring disorders. This project aims to fill gaps identified in the NRAP by examining the validity of genetic-based biomarkers to identify PTSD, PTSD course, and response to PTSD treatment. We plan to leverage extensive existing resources in the STRONG STAR Repository to examine a comprehensive set of genetic and epigenetic markers associated with PTSD. These resources include: (1) a collection of human postmortem tissue of PTSD (n=30) and matched control (n=60) brains; (2) a cohort of service members treated for PTSD with blood collected prior to treatment and at 6 months post-treatment (n=600); and (3) an epidemiologic cohort of Soldiers assessed prior to and after deployment in support of Operations Enduring Freedom, Iraqi Freedom and New Dawn that included blood collection and PTSD assessment at each assessment (n=4,112). Using a combination of whole-genome microarray and sequencing approaches, we will: (1) identify genetic (SNP, mRNA) or epigenetic (DNA methylation, microRNA) alterations in PTSD; (2) characterize the neuronal morphology of selected brain regions in PTSD and matched controls through Golgi impregnation; (3) identify top gene regulatory networks among the identified set of genes across the samples to guide biomarker analyses; and (4) systematically identify, validate, and test biomarkers based on the mRNA, SNPs, DNA methylation, and microRNA markers of identified genes. We have assembled a collaborative team of scientists consisting of a genetic epidemiologist (Dr. Williamson), a psychiatric geneticist (Dr. Gelernter), a geneticist (Dr. Carless), a neuroanatomist (Dr. Selemon), human postmortem experts (Drs. Young, Kleinman, Hyde, Thompson, & Cruz), biostatisticians (Drs. Mintz, Gelfond, Michelek, & Jaffe), and a clinical psychologist (Dr. Litz). In addition, we propose to collaborate with the DoD Integrated Systems Biology group (Drs. Jett & Hammamieh) to leverage SysBioCube in order to gain a systems level perspective of our “-omics” data that will in turn guide our biomarker discovery work. It is expected that this project will be an important first step in filling the genomic and biomarker gaps in PTSD identified by the NRAP and facilitate the development of diagnostic and prognostic biomarker panels to aid in the detection, treatment, and prevention of PTSD.