Identifying DNA Methylation Alterations of Chronic Effects Of Blast and Disturbed Sleep

总结 创伤性脑损伤（TBI）是军队中死亡和疾病的重要原因，据估计， 10-20%的返回伊拉克自由行动/持久自由行动（阿富汗）退伍军人 患有TBI，许多人的症状提示轻度TBI（mTBI）的残留影响未被识别 出院前。认识到重复暴露于爆炸的潜在残余影响，其中之一可能是 mTBI，2020年国防授权法案包括一项规定，要求记录爆炸暴露 在训练和战斗中，为未来的风险缓解提供信息。拟议研究的重点是调查 在作战训练期间暴露于爆炸和相关环境的影响。与国防部合作 沃尔特里德陆军研究所（WRAIR）的调查人员，我们已经获得了匿名的临界质量 军事人员和执法人员参加防爆业务培训课程的血液样本， 我们进行系统的DNA甲基化和转录研究。我们有2387个生物样本标本 沿着人口统计学，症状，和爆炸传感器数据从两个突破和大口径步枪协议 反映了退伍军人由于其特定的军事职业专长（MOS）而遭受的照射 重复职业性超压暴露（ROPE），导致对mTBI的易感性增加， 相关症状。本研究的首要目标是将转录调控扰动与 与慢性并发的生理和心理症状的累积暴露于爆炸。会聚 该领域的证据和我们自己的研究已经揭示了与ROPE相关的分子扰动。 具体地说，我们已经显示了与DNA甲基化（一种高度稳定的表观遗传标记）相关的原始细胞改变， 参与睡眠和昼夜节律功能的基因，促使我们深入研究睡眠障碍的表型， 在拟议的研究中使用绳索的退伍军人。在这里，我们将追求以下目标：1）识别DNA甲基化 在进行中的队列中与累积职业暴露于爆炸相关的扰动; 2）识别DNA 甲基化模式与ROPE和相关的生理和心理症状进行跟踪， 队列;和3）鉴定与MOS退伍军人中累积原始细胞相关的改变的DNA甲基化模式 暴露于本研究新招募的职业爆炸。基因座中的DNA甲基化和转录模式 将在使用MOS招募的退伍军人中调查前2个目标中确定的问题，涉及不同的持续时间， 职业性爆炸暴露谱，以确定这些位点是否也与累积性 爆炸和相关的临床症状，包括睡眠障碍，与共病mTBI，PTSD和/或重大 这些退伍军人的抑郁症这将使我们能够通过以下途径将爆炸引起的分子变化联系起来 DNA甲基化改变长期存在于我们的退伍军人谁遭受慢性冲击波的影响。 这项研究将导致发现DNA甲基化风险标志物，可能有助于识别风险退伍军人 在ROPE的衰弱症状出现之前，可能使我们能够进行临床干预。

SUMMARY Traumatic brain injury (TBI) is a significant cause of death and disease in the armed forces, and it has been estimated that 10-20% of returning Operation Iraqi Freedom/Operation Enduring Freedom (Afghanistan) Veterans have suffered a TBI, with many having symptoms suggestive of the residual effects of mild TBIs (mTBIs) not recognized prior to discharge. In recognition of the latent residual effects of repeated exposures to blast, one of which may be mTBI, The 2020 National Defense Authorization Act includes a provision mandating documentation of blast exposure during both training and combat to inform future risk mitigation. The focus of the proposed study is to investigate the effects of exposures to blast and related symptomology incurred during operational training. In collaboration with DoD Walter Reed Army Institute of Research (WRAIR) investigators, we have obtained a critical mass of anonymized blood samples from military and law enforcement personnel from operational blast training courses, which will allow us to perform systematic DNA methylation and transcriptional studies. We have 2387 biological sample specimens along with demographic, symptom, and blast sensor data from both breaching and large caliber rifle protocols reflecting the exposures incurred by Veterans who because of their specific military occupational specialty (MOS) have repeated occupational overpressure exposure (ROPE), resulting in increased susceptibility to mTBI and associated symptoms. The overarching goal of this study is to link transcriptional regulatory perturbations associated with cumulative exposure to blast to chronic co-occurring physiological and psychological symptoms. Converging evidence in the field and from our own research has revealed molecular perturbations associated with ROPE. Specifically, we have shown blast associated alterations in DNA methylation (a highly stable epigenetic mark) in genes involved in sleep and circadian functioning, motivating our in-depth phenotyping of sleep disturbance in Veterans with ROPE in the proposed study. Here we will pursue the following aims: 1) Identify DNA methylation perturbations associated with cumulative occupational exposure to blast in ongoing cohorts; 2) Identify DNA methylation patterns that track with ROPE and associated physiological and psychological symptoms in ongoing cohorts; and 3) Identify altered DNA methylation patterns associated with cumulative blast in Veterans with MOS exposed to occupational blast newly recruited for this study. DNA methylation and transcriptional patterns in loci identified in the first 2 aims will be investigated in Veterans recruited with MOS involving varying durations and spectrum of exposures to occupational blast to determine whether these loci are also associated with cumulative blast and related clinical symptoms including sleep disturbance, with comorbid mTBI, PTSD and/or Major Depressive Disorder in these Veterans This will allow us to causally link blast-induced molecular changes via DNA methylation alterations that persist long-term in our Veterans who suffer from the chronic effects of blast. This study will lead to discovery of DNA methylation risk markers that may aid in identification of Veterans at risk before debilitating symptoms of ROPE can emerge, potentially allowing us to intervene clinically.