CTBI:CBI Tauopathy in Mice and Human: Neurodegeneration after Repetitive Neurotrauma: Mechanisms and Biomarker Discovery

爆炸暴露是部署在阿富汗的美军创伤性脑损伤的主要原因， 伊拉克，但令人震惊的是，人们对爆炸暴露的病理后果知之甚少，因为很少有人 人类的大脑已经被研究过了。我们研究了500多名身体接触运动员和退伍军人的大脑， 暴露于爆炸和震荡损伤的研究表明，爆炸和震荡冲击损伤都是 与微血管功能障碍、神经炎症、星形细胞增多、过度磷酸化tau蛋白（ptau）相关 慢性创伤性脑病（CTE）是一种创伤后脑病， 神经变性CTE在病理学上被定义为过度磷酸化的tau蛋白在血管周围积聚 （ptau）蛋白质，并导致认知、行为和情绪功能的进行性下降。存在一个临界 需要全面检查更多的退伍军人爆炸伤病例，以确定准确的 病理生物学潜在的后期影响，这些伤害，并开发生物标志物，以检测具体的，但 进化，分子，细胞和解剖学的脑变化引起的爆炸曝光。鉴于30万 退伍军人已经暴露在爆炸中，迫切需要从这些退伍军人中招募大脑捐赠 并分析爆炸对关键大脑过程的影响。了解爆炸的神经病理学- 诱导的大脑变化将确定在生活中检测这些变化的方法， 创伤后神经退化和慢性创伤性脑损伤在这个应用中，我们将使用最大的神经病理学 确认尸检队列的退伍军人暴露于爆炸和震荡损伤，结合强大的 招募工作，以显着增加大脑捐赠者的数量，以确定之间的关系， 爆炸暴露和神经炎症，血脑屏障渗漏，星形细胞变性， 胶质淋巴清除网络和ptau病理学。我们将使用最先进的神经病理学技术 包括定量免疫组织化学、多重免疫荧光、定量聚合酶链反应 反应（qPCR）表达分析，酶联免疫吸附测定（ELISA）， 原位杂交（ISH）和基因表达测定的退伍军人与历史的冲击伤，退伍军人和 接触运动员与历史的震荡性冲击损伤和退伍军人控制，以获得新的见解， 爆炸引起的创伤后神经变性和CTE的分子机制。我们还将 测试APOEε4和TMEM 106 b单倍型状态是否改变这些效应。这项研究将为 旨在鉴定用于检测的新型生物标志物和用于爆炸诱导的早期治疗干预的靶点， 创伤后神经变性和CTE了解潜在的基本病理生理学 暴露后微血管病变、炎症、星形细胞增多、水通道蛋白丢失和加速的ptau病理学 爆炸和震荡冲击损伤将有助于确定新的生物标志物，以检测和治疗CTE， 创伤后神经退行性疾病的研究

Blast exposure is the leading cause of traumatic brain injury among U.S. forces deployed to Afghanistan and Iraq, yet alarmingly little is known about the pathological consequences of blast exposure because so few human brains have been studied. Our studies of over 500 brains of contact sport athletes and military veterans exposed to blast and concussive injury have shown that both blast and concussive impact injuries are associated with microvascular dysfunction, neuroinflammation, astrocytosis, hyperphosphorylated tau (ptau) deposition and the development of chronic traumatic encephalopathy (CTE), a posttraumatic neurodegeneration. CTE is defined pathologically by the perivascular accumulation of hyperphosphorylated tau (ptau) protein and results in progressive decline in cognitive, behavioral and mood function. There is a critical need to comprehensively examine more veteran cases of blast injury in order to determine the precise pathobiology underlying the late-effects of these injuries and to develop biomarkers to detect the specific, yet evolving, molecular, cellular, and anatomical brain changes induced by blast exposure. Given that 300,000 military veterans have been exposed to blast, there is urgency to recruiting brain donation from these veterans and analyzing the effects of blast on critical brain processes. Understanding the neuropathology of blast- induced brain changes will identify ways to detect these alterations during life and to monitor the development of posttraumatic neurodegeneration and CTE. In this application, we will use the largest neuropathologically confirmed autopsy cohort of veterans exposed to blast and concussive injury, in conjunction with a robust recruitment effort to dramatically increase the number of brain donors, to determine the relationship between blast exposure and neuroinflammation, blood brain barrier leakage, astrocytic degeneration, loss of the glymphatic clearance network and ptau pathology. We will use cutting edge neuropathological techniques including quantitative immunohistochemistry, multiplex immunofluorescence, quantitative polymerase chain reaction (qPCR) expression analysis, enzyme-linked immunosorbent assay’s (ELISA), in situ hybridization (ISH) and gene expression assays in veterans with a history of blast injury, veterans and contact sport athletes with a history of concussive impact injury and veteran controls to gain new insights into the molecular mechanisms underlying blast-induced posttraumatic neurodegeneration and CTE. We will also test whether APOEε4 and TMEM106b haplotype status modify these effects. This research will pave the way towards identifying novel biomarkers for detection and targets for early therapeutic intervention in blast-induced posttraumatic neurodegeneration and CTE. Understanding the fundamental pathophysiology underlying microvasculopathy, inflammation, astrocytosis, aquaporin loss and accelerated ptau pathology after exposure to blast and concussive impact injury will help identify novel biomarkers to detect and treat CTE and posttraumatic neurodegeneration in living veterans.