Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy

重复性 mTBI 诱导的神经行为变化和 CTE 样蛋白病

• 批准号: 9190335
• 负责人: KEVIN Ka Wang WANG
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190335
• 关键词: Address; Affect; Aggressive behavior; Aging; Anxiety; Behavior; Biochemical; Biological Assay; Biological Markers; Brain; Brain region; Chronic; Chronic Phase; Clinical Research; Closed head injuries; Cognitive; Cognitive deficits; Confusion; Craniocerebral Trauma; DNA-Binding Proteins; Data; Dementia; Deposition; Development; Diagnosis; Enzyme-Linked Immunosorbent Assay; Genetic Crossing Over; Human; Immunization; Immunoassay; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Impairment; Injury; Knowledge; Lead; Learning; Link; Memory Loss; Mental Depression; Military Personnel; Mission; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Neurologic; Patient Care; Patients; Phase; Phosphorylation; Prevention; Protein Fragment; Proteins; Research; Risk; Rodent; Serum; Symptoms; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Veterans; Wild Type Mouse; Work; base; brain tissue; chronic traumatic encephalopathy; combat; depressive symptoms; experience; extracellular; human subject; improved; link protein; meetings; mild traumatic brain injury; mouse model; neurobehavioral; neurobehavioral test; neuropathology; novel; overexpression; oxidation; protein TDP-43; protein aggregate; tau Proteins; tau aggregation; tau-1; tool

Repetitive mild closed head injury (rCHI) is a common form of mild traumatic brain injury (mTBI) among military personnel in both combat and non-combat missions. rCHI can result in sustained cognitive decline and neurobehavioral changes (such as anxiety and depression-like behaviors) [1]. More recently rCHI has also been linked to the formation of a neurodegenerative condition called chronic traumatic encephalopathy (CTE). CTE is pathologically characterized by protein aggregate deposit found in the cortex and other brain regions, post-mortem. Two major proteins found in these CTE protein deposits are microtubule-associated protein Tau and TAR DNA-binding protein (TDP-43) [2-5]. Patients with CTE may show symptoms of dementia, such as memory loss, confusion, anxiety, depression and aggression, which generally appear years or decade(s) after the occurrence of neurotrauma. The Central Hypothesis to be tested is that chronic cognitive and neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43 proteinopathy development. In addition, the proposed work will not only allow us to test this hypothesis, but also enable us to validate novel CTE biomarkers tests as well as to examine a novel Tau, TDP-43 proteinopathy-based immunotherapy strategy towards improvement of chronic neurobehavioral deficits. Three specific aims are proposed in this application to address the central hypothesis. In Specific Aim 1, we will subject wildtype mice to repetitive close head injury (rCHI) and follow them from subacute to chronic period (up to 18 mo.) to characterize cognitive and neurobehavioral changes, overall neuropathology and their correlation with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation /proteinopathy signatures in brain tissue and biofluid. In Specific Aim 2 we will subject human-tau (hTau) transgenic mice and TDP-43 overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they develop worsened cognitive and neurobehavioral changes, neuropathology and accelerated, exaggerated Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid. Lastly, in Specific Aim 3, we will combine our learning from rCHI models in Aim 1 & 2 to test potential effects of Tau/P-Tau and TDP-43 immunization as novel immunotherapy for reducing rCHI-induced Tau and TDP-43 proteinopathy load and mitigating chronic cognitive, neurobehavioral and neuropathological changes in wildtype, hTau, TDP-43 transgenic and/or hTau/TDP-43 double transgenic mouse lines. This proposed systemic study will advance our understanding of the neurobehavioral (anxiety, depression, cognitive dysfunctions) and their potential linkage to the biochemical/protein changes of aggregation-prone proteins such as Tau and TDP-43 (proteinopathy) and CTE- like neurodegenerative cascade during the chronic phase of TBI. Such knowledge can translate into the ability for VA to devise better management tools and improved Veteran patient care. Our findings will also help us better diagnose chronic TBI including ultrasensitive biofluid-based Tau/P-tau and TDP-43-biomarker tests. Furthermore our research also points to a novel and promising immunotherapeutic strategy to treat such conditions. Taken together, these are all significant biomedical advances consistent with the research mission of the NF/SG VHS and VA and meet the full intent of the RFA. Importantly, the learning from this rodent studies and the immunotherapy approach can rapidly translate into clinical studies with Veterans who are at risk of developing post-TBI CTE.

重复的轻度闭合头部受伤（RCHI）是军事中轻度创伤性脑损伤（MTBI）的常见形式 战斗和非战斗任务中的人员。 RCHI可以导致认知能力下降和 神经行为变化（例如焦虑和抑郁症行为）[1]。最近Rchi也有 与称为慢性创伤性脑病（CTE）的神经退行性疾病的形成有关。 CTE在病理上的特征是在皮质和其他大脑区域中发现的蛋白质骨料沉积物， 验尸。这些CTE蛋白沉积物中发现的两个主要蛋白质是微管相关的蛋白tau 和焦油DNA结合蛋白（TDP-43）[2-5]。 CTE患者可能显示出痴呆症状，此类 作为记忆丧失，混乱，焦虑，抑郁和侵略，通常会出现数年或十年 神经曲菌发生后。要检验的中心假设是慢性认知和 重复MTBI（RCHI）后的神经行为变化与伤害后TAU和TDP-43密切相关 蛋白质病的发育。此外，拟议的工作不仅将使我们能够检验这一假设，而且还可以 还使我们能够验证新颖的CTE生物标志物测试以及检查新型TAU，TDP-43 基于蛋白质疗法的免疫疗法策略改善了慢性神经行为缺陷。三 在本申请中提出了具体目的，以解决中心假设。在特定目标1中，我们将 对野生型小鼠进行重复闭合头部损伤（RCHI），并从亚急性到慢性时期（向上） 至18 mo。）表征认知和神经行为变化，整体神经病理学及其相关性 带有时间依赖性的CTE样tau /p-tau和tdp-43蛋白积累 /蛋白质病特征 组织和生物流体。在特定目标2中，我们将对人塔（HTAU）转基因小鼠和TDP-43进行人体tau（HTAU） 过表达转基因小鼠到Rchi，并从亚急性到慢性时期跟随它们，以检查它们是否是否 发展恶化的认知和神经行为变化，神经病理学和加速，夸张 TAU/TDP-43脑组织和生物流体中的蛋白质病特征。最后，在特定的目标3中，我们将结合我们的 在AIM 1和2中从RCHI模型中学习，以测试TAU/P-TAU和TDP-43免疫的潜在影响 减少RCHI诱导的TAU和TDP-43蛋白质病负荷的新型免疫疗法，并减轻慢性 WildType，HTAU，TDP-43转基因和/或的认知，神经行为和神经病理学变化 HTAU/TDP-43双转基因小鼠系。这项拟议的系统研究将提高我们对 神经行为（焦虑，抑郁，认知功能障碍）及其与 聚集蛋白的生化/蛋白质变化，例如Tau和TDP-43（蛋白质病）和CTE- 像在TBI慢性期间的神经退行性级联反应一样。这样的知识可以转化为能力 VA可以设计更好的管理工具并改善资深患者护理。我们的发现也将帮助我们 更好地诊断慢性TBI，包括超敏感生物流体的TAU/P-TAU和TDP-43-BIOMARKARS测试。 此外，我们的研究还指出了一种新颖而有希望的免疫治疗策略 状况。综上所述，这些都是与研究任务一致的重要生物医学进步 NF/SG VHS和VA，并满足RFA的全部意图。重要的是，从这个啮齿动物那里学习 研究和免疫疗法方法可以迅速转化为与AT的退伍军人 发生TBI CTE后发展的风险。