CAP - Genetic and Epigenetic Alterations as Biomarkers for PTSD Diagnosis

CAP - 遗传和表观遗传改变作为 PTSD 诊断的生物标志物

• 批准号: 10020890
• 负责人: DOUGLAS E WILLIAMSON
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020890
• 关键词: Afghanistan; Aftercare; Amygdaloid structure; Anterior; Area; Attention; Autopsy; Biological Markers; Blood; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Chronic; Clinical; Collection; Corticotropin-Releasing Hormone; DNA Methylation; DRD2 gene; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease Progression; Dopamine Receptor; Dorsal; Early Intervention; Enrollment; Epidemiologist; Epidemiology; Epigenetic Process; FK506 binding protein 5; Freedom; Future; GABA Receptor; Genes; Genetic; Genetic Markers; Genetic Variation; Goals; Golgi Apparatus; Hippocampus (Brain); Human; Individual; Institute of Medicine (U.S.); Iraq; Lateral; Literature; Medial; Messenger RNA; MicroRNAs; Military Personnel; Morphology; Names; Neurons; Onset of illness; Orphan; Pathway Analysis; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Prevention; Prognostic Marker; Psychologist; Receptor Gene; Regulator Genes; Reporting; Research; Resources; Retinoids; Risk; Sampling; Scientist; Soldier; Subgroup; Symptoms; System; Systems Biology; Testing; Tissues; Validation; Vertebral column; Veterans; War; Work; base; biomarker discovery; biomarker panel; cingulate cortex; clinical care; clinically relevant; cohort; combat; density; diagnostic biomarker; dual diagnosis; epigenetic marker; evidence base; frontal lobe; genome wide association study; genomic biomarker; methylation biomarker; microRNA biomarkers; novel diagnostics; operation; pituitary adenylate cyclase activating polypeptide; psychogenetics; receptor; repository; response; service member; treatment response; treatment strategy; whole genome

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.

国家研究行动计划 (NRAP) (2013) 呼吁关注惊人的高 在部署的现役军人和退伍军人中观察到与战斗相关的创伤后应激障碍的比率 其结果是，缓解联盟支持了伊拉克和阿富汗战争。 PTSD (CAP) 的成立是为了 a) 显着推进 PTSD 的治疗策略 包括针对早期、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作为 PTSD 的诊断和预后指标 该项目旨在填补 NRAP 中发现的空白。 检查基于基因的生物标志物识别 PTSD、PTSD 过程的有效性，以及 我们计划利用广泛的现有资源来应对 PTSD 治疗。 STRONG STAR Repository 用于检查一套全面的遗传和表观遗传 与 PTSD 相关的标记包括：(1) 人类的集合。 PTSD（n = 30）和匹配对照（n = 60）大脑的死后组织；（2）一组 接受 PTSD 治疗的服役人员在治疗前和 6 点采集血液 治疗后几个月（n=600）；（3）评估士兵的流行病学队列 部署支持持久自由、伊拉克自由行动之前和之后 和 New Dawn，其中包括每个项目的血液采集和 PTSD 评估 结合使用全基因组微阵列和评估（n=4,112）。 测序方法中，我们将：（1）识别遗传（SNP、mRNA）或表观遗传（DNA） (2)表征神经元形态 通过高尔基体浸渍对 PTSD 中选定的大脑区域和匹配的对照进行研究 (3) 在已识别的基因组中识别顶级基因调控网络 指导生物标志物分析的样本；(4) 系统地识别、验证和测试 基于 mRNA、SNP、DNA 甲基化和 microRNA 标记的生物标记 我们组建了一个由科学家组成的协作团队，其中包括： 遗传流行病学家（Williamson 博士）、精神病遗传学家（Gelernter 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、 Michelek 和 Jaffe）和临床心理学家（Litz 博士）此外，我们建议。 与国防部集成系统生物学小组（Jett 和 Hammamieh 博士）合作 利用 SysBioCube 获得“组学”数据的系统级视角 预计该项目将反过来指导我们的生物标志物发现工作。 这是填补 PTSD 基因组和生物标志物空白的重要第一步 NRAP 并促进诊断和预后生物标志物组的开发 帮助检测、治疗和预防 PTSD。