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年）呼吁关注令人震惊的高水平 在服役人员和退伍军人中观察到的与战斗有关的创伤后应激障碍的发生率 支持伊拉克和阿富汗战争。因此，缓解危机联合会 PTSD（CAP）的形成是为了a）显著推进PTSD的治疗策略 包括对早期、慢性和潜伏发作病例的干预，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 和并发症该项目旨在填补国家行动计划中确定的空白， 检查基于遗传的生物标志物的有效性，以识别PTSD，PTSD过程， PTSD治疗的反应。我们计划利用广泛的现有资源， 强星星知识库检查一套全面的遗传和表观遗传 与创伤后应激障碍相关的标志物这些资源包括：（1）收集人类 创伤后应激障碍（n=30）和匹配对照（n=60）大脑的死后组织;（2）一组 在治疗前和治疗后6个月， 治疗后6个月（n=600）;（3）一个流行病学队列的士兵评估 在部署之前和之后，支持持久自由行动， 和新黎明，包括血液收集和创伤后应激障碍评估， 评估（n= 4，112）。使用全基因组微阵列和 测序方法，我们将：（1）确定遗传（SNP，mRNA）或表观遗传（DNA 甲基化，microRNA）改变;（2）表征神经元形态 通过高尔基体浸渍，在PTSD和匹配的对照组中选择脑区域;（3） 在所鉴定的基因组中鉴定跨所述基因组的顶级基因调控网络。 样品，以指导生物标志物分析;和（4）系统地识别，验证和测试 基于mRNA、SNP、DNA甲基化和microRNA标记的生物标志物， 识别基因我们组建了一个科学家合作小组， 遗传流行病学家（威廉姆森博士），精神病遗传学家（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 (Drs. Young，Kleinman，Hyde，Thompson和Cruz），生物统计学家（Mintz，Gelfond， Michelek，& Jaffe）和临床心理学家（Dr. Litz）。此外，我们建议 与国防部综合系统生物学小组（杰特和哈马米博士）合作， 利用SysBioCube来获得我们的“组学”数据的系统级透视图 这反过来将指导我们的生物标志物发现工作。预计该项目将在 这是填补PTSD基因组和生物标志物空白的重要第一步， NRAP和促进诊断和预后生物标志物小组的发展 帮助检测、治疗和预防PTSD。