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: 10023154
• 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/10023154
• 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）引起了人们对令人震惊的高度的关注 在部署的服务成员和退伍军人之间观察到与战斗有关的PTSD的比率 支持伊拉克和阿富汗的战争。结果，减轻的财团 PTSD（CAP）被形成a）显着提高PTSD的治疗策略 包括对早期，慢性和潜在发病案例的干预措施，以及b）识别和 确认与临床相关的生物标志物作为PTSD的诊断和预后指标 和共同出现的疾病。该项目旨在填补NRAP中确定的空白 检查基于遗传的生物标志物鉴定PTSD，PTSD课程和 对PTSD治疗的反应。我们计划利用广泛的现有资源 强大的恒星存储库，以检查一组综合的遗传和表观遗传学 与PTSD相关的标记。这些资源包括：（1）人类的集合 PTSD（n = 30）和匹配的对照（n = 60）大脑的验尸组织； （2）一群 在治疗前用血液和6点收集血液治疗的服务员 治疗后月（n = 600）; （3）评估的士兵的流行病学队列 在部署之前和之后支持持久自由的行动，伊拉克自由 和新的黎明，其中包括血液收集和PTSD评估 评估（n = 4,112）。结合全基因组微阵列和 测序方法，我们将：（1）识别遗传（SNP，mRNA）或表观遗传学（DNA） PTSD中的甲基化，microRNA）的改变； （2）表征神经元形态 通过高尔基体浸渍，PTSD中选定的大脑区域和匹配的对照； （3） 识别跨整个基因的基因调节网络 引导生物标志物分析的样品； （4）系统识别，验证和测试 基于MRNA，SNP，DNA甲基化和microRNA标记的生物标志物 确定的基因。我们组建了一个由科学家组成的协作团队 遗传流行病学家（Williamson博士），精神病遗传学家（Gelernter博士）， 神经解剖学家（Selemon博士）遗传学家（Carless博士），人类邮政专家 （Young博士，Kleinman，Hyde，Thompson和Cruz），生物统计学家（Mintz博士，Gelfond，Gelfond， Michelek和Jaffe），以及临床心理学家（Litz博士）。此外，我们建议 与国防部集成系统生物学小组（Jett＆Hammamieh博士）合作 利用sysbiocube，以获得我们的“ - 组”数据的系统级别的观点 反过来，这将指导我们的生物标志物发现工作。预计这个项目将是 填补PTSD中基因组和生物标志物差距的重要第一步 NRAP并促进诊断和预后生物标志物面板的开发 帮助检测，治疗和预防PTSD。