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。颅脑损伤是导致 武装部队中的死亡和疾病以及从伊拉克战争(伊拉克自由行动；OIF)和阿富汗(持久自由行动；OEF)返回的退伍军人。据估计，这些回国的退伍军人中有10%-20%患有脑损伤，在许多情况下，甚至在退伍前都没有得到诊断。与脑外伤相关的精神病理症状包括情绪和焦虑障碍、创伤后应激障碍、自杀以及认知能力下降和注意力和记忆障碍。这些症状可能在受伤数年后出现，导致误诊和缺乏适当的护理和治疗。由于有如此多的退伍军人患有脑外伤和相关的精神病理，了解脑外伤的分子电路对我们退伍军人的健康和生产力至关重要。为此，我们建议研究BLAST相关脑损伤的表观遗传学机制。具体地说，我们将确定在军事人员和过压爆炸动物模型中，重复爆炸暴露引起的DNA甲基化异常。通过表观遗传变化(如DNA甲基化)调节基因表达是大脑对包括冲击波暴露在内的经验做出反应的一种方式。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，从而导致在以后的生活中出现精神症状。结合来自反复爆炸暴露的动物模型的数据，以及来自反复暴露于爆炸事件的军事破碎者亚群的人类受试者的数据，将使我们能够确定与动物爆炸暴露相关的表观遗传学改变是否出现在人类爆破者的相同基因或遗传途径中，并立即产生翻译影响。这是一项高影响力的研究，不仅将加深我们对爆炸性脑外伤潜在分子机制的了解，还可能为未来的治疗干预识别基因靶点，并显著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.