Prospective Determination of the Epigenetic Response to Trauma

 描述(由申请人提供)：世界各地的流行病学研究证明，创伤事件的发生率很高，包括危及生命的事故、强奸、战斗、肢体暴力、目睹他人死亡或受伤以及自然灾害。这种创伤经历极大地增加了患精神疾病的可能性，包括创伤后应激障碍(PTSD)、抑郁或药物滥用。尽管超过80%的人会经历创伤性事件，但只有一小部分人会发展成精神疾病 疾病，表明生物风险因素起着很大的作用。然而，目前还没有生物因素可用于前瞻性地监测易受感染的个体。最近的表观遗传学研究报告了那些经历过与精神病理学相关的创伤的人之间存在广泛的DNA甲基化差异。由于DNA甲基化的变化会随着时间的推移而积累，因此在创伤相关症状发展之前，创伤暴露的分子特征可能会非常明显。然而，表观遗传变化的时间表和持久性仍然不清楚。这项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，并表征发生剧烈(最初几周至1个月)和稳定(至3个月)的DNA甲基化变化。我们还将评估4个特定的应激反应基因(FKBP5、SLC6A4、BDNF和COMT)的变化。最后，我们将评估在创伤后3个月，DNA甲基化的急性变化是否可以预测精神症状和恐惧增强的惊吓反应，这是一种与创伤后应激障碍相关的生理表型。这项研究在关注急性表观遗传机制方面具有很高的新颖性；此外，它还关注创伤暴露的心理生理表型，而不是NIMH研究领域标准中倡导的DSM诊断。分析单位将包括分子(DNA甲基化)、生理(恐惧加剧的惊吓)和自我报告(创伤后应激障碍症状量表、贝克抑郁问卷)作为创伤反应的维度测量。这项研究将在分子水平上为创伤的病理生理学提供亟需的见解，并为早期干预研究奠定基础。识别表观基因组对创伤事件的反应将为更大规模的前瞻性研究提供初步数据，有助于早期发现创伤相关的精神病理学。

 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.