Epigenetic Mechanisms in Blast Related Traumatic Brain Injury

 描述（由申请人提供）： 创伤性脑损伤（TBI）每年影响170万美国人。TBI是导致 武装部队和从伊拉克战争（伊拉克自由行动; OIF）和阿富汗战争（持久自由行动; OEF）返回的退伍军人中的死亡和疾病。据估计，这些退伍军人中有10-20%患有TBI，并且在许多情况下甚至在出院前没有被诊断出来。与TBI相关的精神病理学症状包括情绪和焦虑障碍、创伤后应激障碍、自杀倾向以及认知能力下降伴注意力和记忆力缺陷。这些症状可能在受伤后数年出现，导致误诊和缺乏适当的护理和治疗。由于返回的退伍军人数量惊人，持续TBI和相关的精神病理学，了解TBI的分子电路对我们退伍军人群体的健康和生产力至关重要。为此，我们建议调查表观遗传机制在爆炸相关的TBI。具体来说，我们将确定DNA甲基化异常诱导响应重复爆炸暴露在军事人员和动物模型的爆炸压力。由表观遗传变化（如DNA甲基化）介导的基因表达调节是大脑对经历（包括爆炸暴露）做出反应时创造新的稳态的一种方式。我们将利用最先进的测序和生物信息学技术来识别与爆炸暴露相关的异常DNA甲基化特征。这种甲基化异常可能导致基因表达异常，从而导致以后出现精神症状。将来自重复爆炸暴露的动物模型的数据与来自暴露于重复爆炸事件的军事Breacher人员亚群的人类受试者的数据相结合，将使我们能够确定与动物中的爆炸暴露相关的表观遗传改变是否在人类Breacher中的相同基因或遗传途径中观察到，并具有直接的翻译影响。这是一项高影响力的研究，不仅将进一步加深我们对爆炸相关TBI的分子机制的理解，而且还可能导致识别未来治疗干预的基因靶点，并大大改善我们退伍军人的医疗保健。

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects 1.7 million Americans each year. TBI is a significant cause of death and disease in the armed forces and the veteran population returning from wars in Iraq (Operation Iraqi Freedom; OIF) and Afghanistan (Operation Enduring Freedom; OEF). It has been estimated that that 10-20% of these returning veterans have suffered a TBI, and in many cases were not even diagnosed prior to discharge. Psychopathological symptoms associated with TBI include mood and anxiety disorders, post-traumatic stress disorder, suicidality, and diminished cognitive capacity with deficits in attention and memory. These symptoms can arise years after time of injury, leading to misdiagnosis and lack of proper care and treatment. With such staggering numbers of returning Veterans sustaining TBI and associated psychopathologies, understanding the molecular circuitry of TBI is critically important to the health and productivity of our Veteran population. To this end we propose to investigate epigenetic mechanisms' in blast-related TBI. Specifically, we will identify DNA methylation abnormalities induced in response to repeated blast exposure in both military personnel and animal model of blast-over-pressure. Modulation of gene expression mediated by epigenetic changes such as DNA methylation is one way the brain creates new homeostasis in response to experience, including blast exposure. We will utilize state-of-the-art sequencing and bioinformatics technologies to identify aberrant DNA methylation signatures associated with blast exposure. Such methylation abnormalities can confer gene expression abnormalities that can lead to development of psychiatric symptoms later in life. Combining data from animal model of repeated blast exposure together with data from human subjects from subpopulation of military Breacher personnel with exposure to repeated blast events, will allow us to determine whether the epigenetic alterations associated with blast exposure in animals are seen in the same genes or genetic pathways in human Breachers with immediate translational impact. This is a high-impact study that will not only further our understanding of the molecular mechanisms underlying blast-related TBI, but may also lead to identification of gene targets for future therapeutic intervention and substantially improve medical care of our veterans.