Prospective Determination of the Epigenetic Response to Trauma

对创伤的表观遗传反应的前瞻性测定

• 批准号: 9035131
• 负责人: Tanja Jovanovic
• 金额: $ 27.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-13 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035131
• 关键词: Accidents; Acute; Address; Adult; Advocate; African American; Beck depression inventory; Biological; Biological Factors; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell division; Cessation of life; Child Abuse; Clinical; Clinical assessments; DNA; DNA Methylation; DNA Sequence Alteration; Data; Development; Diagnosis; Diagnostic and Statistical Manual of Mental Disorders; Disease; Early Diagnosis; Early Intervention; Environment; Epidemiologic Studies; Epigenetic Process; Exposure to; Female; Forcible intercourse; Foundations; Fright; Functional disorder; Gender; Gene Expression; Genes; Genetic Predisposition to Disease; Genome; Home environment; Individual; Injury; Intervention Studies; Investigation; Life; Low income; Measures; Mental Depression; Mental disorders; Methylation; Modification; Molecular; Molecular Profiling; Monitor; National Institute of Mental Health; Natural Disasters; Patient Self-Report; Persons; Phenotype; Physiological; Population; Post-Traumatic Stress Disorders; Prospective Studies; Psychopathology; Psychophysiology; Recording of previous events; Reporting; Research; Research Infrastructure; Risk; Risk Factors; Role; Saliva; Sampling; Severities; Social support; Stress; Substance abuse problem; Suicide; Surveys; Symptoms; Time; TimeLine; Trauma; Violence; biological adaptation to stress; cohort; combat; depressive symptoms; effective intervention; epigenetic marker; epigenome; experience; genome-wide; high risk; inner city; insight; novel; pediatric trauma; prospective; psychiatric symptom; public health relevance; response; trauma centers; traumatic event

 DESCRIPTION (provided by applicant): Epidemiological studies worldwide have documented a high rate of exposure to traumatic events, including life-threatening accidents, rape, combat, physical violence, witnessing the death or injury of others and natural disasters. Such traumatic experiences significantly increase the likelihood of having a mental illness, including posttraumatic stress disorder (PTSD), depression or substance abuse. Although more than 80% of the population will experience a traumatic event, only a fraction of those will develop a mental illness, suggesting a large role for biological risk factors. However, there are currently no biological factors that can be used to prospectively monitor vulnerable individuals. Recent epigenetic studies report extensive DNA methylation differences in those who have experienced trauma that associate with psychopathology. Because changes in DNA methylation accumulate over time, the molecular signature of trauma exposure may be evident substantially before trauma-related symptoms develop. However, the timeline and permanence of epigenetic changes are still unclear. This study will address this question by leveraging infrastructure from an ongoing investigation (R01 MH094757; PI Ressler) that is prospectively characterizing trauma victims from Atlanta's inner-city Level 1 trauma center. To evaluate how DNA methylation changes over time, we will prospectively collect DNA samples for the first 3 months after a traumatic event and characterize the DNA methylation changes that occur acutely (within the first weeks up to 1 month) and stably (through 3 months). We will also evaluate changes in 4 specific stress-response genes (FKBP5, SLC6A4, BDNF and COMT). Finally, we will evaluate whether acute changes in DNA methylation predict psychiatric symptoms and fear-potentiated startle response, a physiological phenotype that has been associated with PTSD, at 3 months after the trauma. This study is highly novel in its focus on acute epigenetic mechanisms; furthermore, it focuses on psychophysiological phenotypes of trauma exposure rather than DSM diagnoses as advocated in the NIMH Research Domains Criteria. The units of analyses will include molecular (DNA methylation), physiological (fear-potentiated startle), and self-report (PTSD Symptom Scale, Beck Depression inventory) measures as dimensional measures of trauma response. This research will provide much needed insight into the pathophysiology of trauma on a molecular level and lay a foundation for early intervention studies. Identification of how the epigenome responds to a traumatic event will provide preliminary data for larger prospective studies that facilitate early detection of trauma-related psychopathology.

 描述（由申请人提供）：世界各地的流行病学研究记录了遭受创伤性事件的比例很高，包括危及生命的事故、强奸、打斗、身体暴力、目睹他人死亡或受伤以及自然灾害。此类创伤经历显着增加患精神疾病的可能性，包括创伤后应激障碍（PTSD）、抑郁症或药物滥用。虽然超过 80% 的人会经历创伤性事件，但其中只有一小部分人会产生心理创伤 疾病，表明生物危险因素发挥着重要作用。然而，目前还没有生物因素可用于前瞻性监测弱势个体。最近的表观遗传学研究报告称，经历过与精神病理学相关的创伤的人体内存在广泛的 DNA 甲基化差异。由于 DNA 甲基化的变化会随着时间的推移而累积，因此在创伤相关症状出现之前，创伤暴露的分子特征可能就已经很明显了。然而，表观遗传变化的时间线和持久性仍不清楚。本研究将通过利用正在进行的调查（R01 MH094757；PI Ressler）的基础设施来解决这个问题，该调查前瞻性地描述了亚特兰大市中心一级创伤中心的创伤受害者的特征。为了评估 DNA 甲基化如何随时间变化，我们将前瞻性地收集创伤事件后前 3 个月的 DNA 样本，并表征急剧发生（前几周至 1 个月内）和稳定发生（整个 3 个月）的 DNA 甲基化变化。我们还将评估 4 个特定应激反应基因（FKBP5、SLC6A4、BDNF 和 COMT）的变化。最后，我们将评估创伤后 3 个月时 DNA 甲基化的急剧变化是否可以预测精神症状和恐惧增强惊吓反应（一种与 PTSD 相关的生理表型）。这项研究非常新颖，重点关注急性表观遗传机制。此外，它侧重于创伤暴露的心理生理表型，而不是 NIMH 研究领域标准中提倡的 DSM 诊断。分析单位将包括分子（DNA 甲基化）、生理（恐惧增强惊吓）和自我报告（PTSD 症状量表、贝克抑郁量表）测量作为创伤反应的维度测量。这项研究将为分子水平上的创伤病理生理学提供急需的见解，并为早期干预研究奠定基础。确定表观基因组如何响应创伤事件将为更大规模的前瞻性研究提供初步数据，从而促进创伤相关精神病理学的早期发现。