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阿富汗的美军造成脑外伤的主要原因 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，因为很少有人知道 人类的大脑已经被研究过。我们对 500 多名接触运动运动员和退伍军人的大脑进行了研究 暴露于爆炸和震荡伤害已经表明，爆炸和震荡冲击伤害都是 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）的沉积和发展，这是一种创伤后疾病 神经变性。 CTE 的病理学定义是血管周围过度磷酸化 tau 蛋白的积累 (ptau) 蛋白质，会导致认知、行为和情绪功能逐渐下降。有一个关键的 需要综合考察更多老兵爆炸伤案例，才能准确判断 这些损伤的后期影响背后的病理生物学，并开发生物标志物来检测特定的、尚未 爆炸暴露引起的大脑进化、分子、细胞和解剖学变化。鉴于 300,000 退伍军人遭遇爆炸，招募退伍军人脑捐献刻不容缓 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检测生命期间这些变化并监测发育的方法 创伤后神经变性和 CTE。在此应用中，我们将使用最大的神经病理学 经尸检证实，暴露于爆炸和震荡损伤的退伍军人群体，并结合了强有力的证据 招募工作以大幅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、星形胶质细胞变性、神经细胞丧失 类淋巴清除网络和 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（qPCR）表达分析，酶联免疫吸附测定（ELISA）， 对有爆炸伤史的退伍军人、退伍军人和 联系有脑震荡损伤史的体育运动员和退伍军人控制措施，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 TMEM106b 单倍型状态是否会改变这些效应。这项研究将为 旨在确定用于检测的新型生物标志物和用于爆炸引起的早期治疗干预的目标 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 ptau 病理学 爆炸和震荡冲击损伤将有助于识别新的生物标志物来检测和治疗 CTE 和 活着的退伍军人的创伤后神经变性。