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和阿富汗的美军创伤性脑损伤的主要原因 然而，令人担忧的是，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。我们对500多名接触性运动运动员和退伍军人的大脑进行了研究 暴露于冲击波和脑震荡伤表明，冲击波和脑震荡冲击伤都是 与微血管功能障碍、神经炎症、星形细胞增多症、过度磷酸化tau(Ptau)相关 慢性创伤性脑病(CTE)的沉积与发展 神经退行性变。CTE的病理定义是过度磷酸化的tau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。有一个关键的问题 需要全面检查更多的退伍军人爆炸伤病例，以确定准确的 这些损伤的晚期效应的病理生物学基础，并开发生物标记物来检测特定的、尚未 冲击波暴露引起的进化的、分子的、细胞的和解剖的大脑变化。考虑到这30万 退伍军人被曝爆炸，向这些老兵募捐脑力迫在眉睫 以及分析BLAST对关键脑过程的影响。了解冲击波的神经病理学- 诱发的大脑变化将确定在生活中检测这些变化并监控发育的方法 创伤后神经变性和CTE。在本应用程序中，我们将使用最大的神经病理学 暴露在冲击波和脑震荡伤中的退伍军人的确认尸检队列，连同一个健壮的 招聘努力大幅增加了脑捐赠者的数量，以确定两者之间的关系 冲击波暴露与神经炎症、血脑屏障渗漏、星形细胞变性、 淋巴清扫网络与ptau病理。我们将使用尖端的神经病理技术 包括定量免疫组织化学、多重免疫荧光、定量聚合酶链 反应(QPCR)表达分析，酶联免疫吸附试验(ELISA)，在 有冲击伤病史的退伍军人、退伍军人和退伍军人的原位杂交和基因表达分析 联系有脑震荡损伤病史和经验丰富的运动员，以获得新的见解 冲击波诱导的创伤后神经变性和CTE的分子机制。我们还将 测试载脂蛋白ε4和TMEM106b单倍型状态是否会改变这些效应。这项研究将为 寻找新的检测生物标志物和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 冲击伤和脑震荡伤将有助于识别新的生物标志物来检测和治疗CTE和 活着的退伍军人中的创伤后神经变性。

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.