Epigenetic Mechanisms in Blast Related Traumatic Brain Injury

爆炸相关脑外伤的表观遗传机制

• 批准号: 8985468
• 负责人: FATEMEH G HAGHIGHI
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985468
• 关键词: Aberrant DNA Methylation; Address; Affect; Afghanistan; American; Animal Model; Animals; Anxiety; Anxiety Disorders; Area; Attention; Biochemical; Bioinformatics; Blast Cell; Blood; Blood Tests; Blood specimen; Brain; Brain region; Caring; Cause of Death; Centers for Disease Control and Prevention (U.S.); Chronic; Cognitive; Complex; Control Animal; DNA Methylation; Data; Development; Devices; Diagnosis; Disease; Epigenetic Process; Event; Exposure to; Freedom; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genomic approach; Genomics; Headache; Health; Homeostasis; Human; Human Resources; Impairment; Individual; Injury; Iraq; Law Enforcement; Lead; Life; Light; Link; Long-Term Effects; Matched Group; Mediating; Medical; Memory; Methods; Methylation; Military Personnel; Modification; Molecular; Mood Disorders; Neurobehavioral Manifestations; Occupational Exposure; Pathway interactions; Population; Post-Traumatic Stress Disorders; Productivity; Psychopathology; Reporting; Research; Sampling; Services; Sleep; Specimen; Suicide; Symptoms; Technology; Therapeutic Intervention; Time; Translating; Traumatic Brain Injury; United States; Veterans; War; arm; associated symptom; career; chronic traumatic encephalopathy; clinically relevant; cognitive capacity; emotional symptom; experience; human subject; improved; interest; member; mild traumatic brain injury; neurobehavioral test; neurobiological mechanism; neuropathology; operation; physical symptom; pressure; psychiatric symptom; public health relevance; response; trait; traumatic event

 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.

 描述（由申请人提供）： 脑外伤（TBI）每年影响170万美国人。 TBI是 武装部队的死亡与疾病以及从伊拉克战争（伊拉克自由行动； OIF行动）和阿富汗（持久自由行动； OEF行动）返回的退伍军人。据估计，这些返回的退伍军人中有10-20％遭受了TBI的侵害，在许多情况下，甚至没有在出院前被诊断出。与TBI相关的心理病理症状包括情绪和焦虑症，创伤后应激障碍，自杀性以及注意力和记忆力缺陷的认知能力降低。这些症状可以在受伤后几年出现，导致诊断和缺乏适当的护理和治疗。随着许多维持TBI和相关心理病理学的返回的退伍军人，了解TBI的分子回路对我们的退伍军人人口的健康和生产力至关重要。为此，我们建议研究与爆炸有关的TBI中的表观遗传机制。具体而言，我们将确定由于军事人员的反复爆炸和爆炸性爆炸模型的反复暴露而引起的DNA甲基化异常。通过表观遗传变化（例如DNA甲基化）介导的基因表达的调节是大脑对经验（包括爆炸暴露）产生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。这种甲基化异常会遇到基因表达异常，从而导致生活中精神病的发展。将重复爆炸的动物模型的数据与人类受试者的数据结合在一起，来自军事违规人员的亚群和暴露于重复的爆炸事件的数据，将使我们能够确定在人类违规者中是否在具有直接转换影响的人类违规者中看到与动物爆炸相关的表观遗传改变。这是一项高影响力的研究，不仅我们将进一步了解与爆炸相关的TBI的分子机制，而且还可能导致鉴定出未来治疗干预的基因靶标，并实质上改善对退伍军人的医疗护理。