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

CTBI：小鼠和人类的 CBI Tau 蛋白病：重复性神经创伤后的神经变性：机制和生物标志物发现

• 批准号: 10553627
• 负责人: Ann C. McKee
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553627
• 关键词: Acceleration; Accelerometer; Afghanistan; Age; Anatomy; Astrocytes; Astrocytosis; Autopsy; Behavioral; Biological Markers; Blast Injuries; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Concussion; Chronic; Cognitive; Deposition; Detection; Development; Environment; Enzyme-Linked Immunosorbent Assay; Exposure to; Extravasation; Frequencies; Functional disorder; Gene Expression Profiling; Goals; Haplotypes; Helmet; Human; Immunofluorescence Immunologic; Immunohistochemistry; In Situ Hybridization; Inflammation; Injury; Iraq; Late Effects; Life; Measures; Mediating; Methods; Microvascular Dysfunction; Molecular; Monitor; Moods; Mus; Nerve Degeneration; Nervous System Trauma; Pathologic; Pathology; Pharmacotherapy; Polymerase Chain Reaction; Process; Publishing; Recording of previous events; Research; Resources; Tauopathies; Techniques; Testing; Therapeutic Intervention; Traumatic Brain Injury; Variant; Vascular Diseases; Veterans; apolipoprotein E-4; biomarker discovery; blast exposure; chronic traumatic encephalopathy; cohort; contact sports; experience; glymphatic clearance; glymphatic system; head impact; hyperphosphorylated tau; innovation; insight; military veteran; neuroinflammation; neuropathology; novel marker; recruit; tau Proteins; tau aggregation; wasting; water channel

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.

爆炸暴露是部署到阿富汗和 伊拉克对爆炸暴露的病理后果知之甚少，因为很少 人的大脑已经被研究。我们研究了500多个大脑的接触运动员和退伍军人 暴露于爆炸和脑震荡的表明，爆炸和脑震荡损伤都是 与微血管功能障碍，神经炎症，星形细胞增多症，高磷酸化TAU（PTAU）相关 慢性创伤性脑病（CTE）的沉积和发展，一种创伤后 神经变性。 CTE是通过血管周围的过度磷酸化tau的血管周定义的 （PTAU）蛋白质并导致认知，行为和情绪功能的逐渐下降。有关键 需要全面检查更多的爆炸损伤病例以确定精度 这些伤害的晚期作用的病理生物学，并开发生物标志物以检测特定，但 爆炸暴露引起的发展，分子，细胞和解剖学大脑变化。考虑到300,000 退伍军人已经暴露于爆炸，有迫切需要从这些退伍军人那里招募大脑捐款 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 - 诱发的大脑变化将确定在生活中检测这些改变并监测发展的方法 创伤后神经变性和CTE。在此应用中，我们将在此应用程序上使用最大的神经病理学 确认的退伍军人尸检队列与强大的 招募工作以显着增加大脑捐助者的数量，以确定 爆炸暴露和神经炎症，血脑屏障泄漏，星形细胞变性，丧失 胶囊清除网络和PTAU病理学。我们将使用尖端神经病理技术 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，酶联免疫吸附测定（ELISA），在 爆炸史，退伍军人和 联系具有脑震荡撞击史和退伍军人控制史的运动运动员，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。我们也会 测试APOEε4和TMEM106B单倍型状态是否会修改这些效果。这项研究将铺平道路 旨在识别用于检测的新型生物标志物，并在爆炸诱导的早期热干预的靶标 创伤后神经变性和CTE。了解基本的病理生理基础 暴露后，微举行，感染，星形胶质细胞增多症，水通道蛋白丧失和加速PTAU病理 爆炸和脑震荡损伤将有助于识别新型的生物标志物来检测和治疗CTE和 在活体退伍军人中创伤后神经退行性。