Delayed and Progressive Emergence of CTE- and Psychiatric-like Pathologies after Repetitive Mild TBI

重复轻度 TBI 后 CTE 和精神病样病理的延迟和进行性出现

• 批准号: 10044414
• 负责人: Donald M Kuhn
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 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/10044414
• 关键词: Ablation; Acetylation; Acute; Afghanistan; Anxiety; Appearance; Astrocytes; Autopsy; Behavior Disorders; Behavioral; Brain; CSF1R gene; Chronic; Clinical; Clinical Trials; Cognitive deficits; Complex; Craniocerebral Trauma; Data; Deacetylation; Depression and Suicide; Development; Disease; Enzymes; Equilibrium; Exposure to; Frequencies; Functional disorder; Gliosis; Goals; HDAC6 gene; Head; Health; Healthcare; Histone Deacetylase Inhibitor; Human; Impaired cognition; Individual; Inflammation; Injury; Iraq; Lead; Long-Term Effects; Macrophage Colony-Stimulating Factor Receptor; Medical; Mental Depression; Mental disorders; Microglia; Microtubule Stabilization; Military Personnel; Mission; Modeling; Modification; Motion; Mus; Nature; Nerve Degeneration; Neurological outcome; Neurons; Outcome; Parkinson Disease; Pathologic; Pathology; Phosphorylation; Prevention; Publishing; Research; Seeds; Sleep; Sleep Disorders; Symptoms; TBI treatment; Tauopathies; Testing; Therapeutic Intervention; Time; Traumatic Brain Injury; Veterans; Vision; Work; base; behavioral outcome; chronic traumatic encephalopathy; clinically significant; combat zone; comorbidity; cost; effective therapy; experimental study; head impact; humanized mouse; inhibitor/antagonist; mild traumatic brain injury; military service; military veteran; mouse model; neuroinflammation; neuropathology; novel; novel therapeutics; outcome forecast; prevent; service member; tau Proteins; tau phosphorylation; tau-1; treatment duration; virtual; white matter

Project Summary/Abstract Traumatic brain injury (TBI) has been referred to as the “signature injury” of recent military combat operations in Iraq and Afghanistan. The form of TBI that is most prevalent among military service members and Veterans is repetitive, mild TBI, or rmTBI. Apart from the immediate effects of a head injury, rmTBI is also associated with a number of significant and chronic co-morbid conditions including cognitive dysfunction, sleep disorders, alterations in visual function, and psychiatric complications (e.g., depression, suicide, anxiety). rmTBI and its co-morbid conditions exact a steep toll on military personnel and Veterans and the cost to the nation of TBI is estimated to be $60 billion annually. The mechanisms by which rmTBI alters brain function are not well understood and all clinical trials of new therapies for TBI thus far have failed. Therefore, an effective treatment for TBI does not exist. Perhaps the most alarming aspect of rmTBI is the possibility that repeated mild impacts to the head do not cause clinically significant or recognizable symptoms but set in motion a cascade which has an endpoint of neurodegeneration and psychiatric illness. The primary goals of this application are to 1) refine and validate a humanized mouse model of rmTBI and 2) test two new mechanism-based therapies for the long-term consequences of rmTBI. These goals will be achieved by employing a new model of rmTBI that is very mild, even after as many as 20 head impacts, and which does not result in any behavioral or neuronal pathology at the end of the treatment period. We include preliminary data showing that rmTBI results in a delayed and progressive emergence of increased reactive gliosis and inflammation along white matter tracts, and increases in the pathologic form of tau, a microtubule stabilizing molecule. In addition, this model of rmTBI results in slowly developing cognitive deficits and psychiatric-like disorders (e.g., anxiety and depression), neither of which are evident immediately after the rmTBI course of treatment. These neuronal and behavioral outcomes are hallmark signs of chronic traumatic encephalopathy (CTE) and have been observed in postmortem brains of military service members exposed to rmTBI. Two new drugs will be tested as therapies for rmTBI and include an inhibitor of histone deacetylase 6 (HDAC6) and a colony-stimulating factor 1 receptor (CSFR1) inhibitor that ablates CNS microglia. The rationale behind the use of an HDAC6 inhibitor for treating rmTBI is compelling for several reasons. First, modification of tau by acetylation protects it from aggregation (i.e., its pathological form) by inhibiting its phosphorylation. Second, HDAC6 has been identified as the specific enzyme that deacetylates tau. Deacetylation of tau allows for modification of tau by phosphorylation. Third, inhibition of HDAC6 should shift the balance of acetylation/phosphorylation to favor acetylation and thereby protect tau against pathological aggregation in brain. The rationale behind the use of a CSF1R inhibitor is likewise compelling and strong because rmTBI results in significant increases in microglial activation which then causes a secondary activation of astrocytes. This increased glial reactivity results in neuronal damage. By ablating microglia, a CSF1R inhibitor should prevent activation of both microglia and astrocytes and reduce the CTE-like damage that occurs in CTE. The effects of rmTBI will be studied over a chronic time-frame in mice to simulate the slow-developing neuropathologies and behavioral disorders seen in humans after repeated head injuries. Treatment will not begin until after exposure of mice to repetitive head impacts in order to simulate a clinical situation more closely. It is hypothesized that inhibition of HDAC6 or CSF1R after rmTBI will prevent or reduce the development of CTE-like tau pathology. It is hypothesized further that prevention of the formation of tauopathies with these treatments will reduce the chronic co-morbid conditions that develop with high frequency after rmTBI to include cognitive dysfunction, alterations in vision and sleep, and depression- and anxiety-like behavioral disorders. This project has high translational relevance for the VA health care mission.

项目概要/摘要 创伤性脑损伤（TBI）被称为近期军事作战行动的“标志性损伤” 在伊拉克和阿富汗，创伤性脑损伤在军人和退伍军人中最为常见。 重复性轻度 TBI 或 rmTBI 除了头部受伤的直接影响外，rmTBI 也与之相关。 患有许多严重的慢性共病，包括认知功能障碍、睡眠障碍、 视觉功能改变和精神并发症（例如抑郁、自杀、焦虑）。 共病对军事人员和退伍军人造成巨大损失，TBI 给国家造成的损失是 据估计，每年 rmTBI 改变大脑功能的机制尚不清楚。 据了解，迄今为止所有针对 TBI 新疗法的临床试验都失败了，因此，有效的治疗方法。 TBI 并不存在，也许 rmTBI 最令人担忧的方面是重复轻微影响的可能性。 头部不会引起临床上显着或可识别的症状，但会引发连锁反应， 该应用程序的主要目标是 1) 完善。 并验证 rmTBI 人源化小鼠模型，2) 测试两种新的基于机制的疗法 rmTBI 的长期影响将通过采用新的 rmTBI 模型来实现。 非常轻微，即使在头部受到多达 20 次撞击后，也不会导致任何行为或神经系统问题 我们提供的初步数据表明 rmTBI 会导致治疗结束时的病理结果。 沿着白质束延迟和渐进地出现反应性神经胶质增生和炎症增加， 此外，这种 rmTBI 模型中的 tau 蛋白（一种微管稳定分子）的病理形式也有所增加。 导致缓慢发展的认知缺陷和类似精神疾病（例如焦虑和抑郁）， rmTBI 疗程结束后，这两种情况均不明显。 结果是慢性创伤性脑病（CTE）的标志性症状，并且已在 暴露于 rmTBI 的军人死后大脑将作为治疗方法进行测试。 用于 rmTBI，包括组蛋白脱乙酰酶 6 (HDAC6) 抑制剂和集落刺激因子 1 受体 (CSFR1) 抑制剂可消除 CNS 小胶质细胞 使用 HDAC6 抑制剂进行治疗的基本原理。 rmTBI 之所以引人注目，有几个原因：首先，通过乙酰化修饰 tau 可防止其聚集。 (即其病理形式)通过抑制其磷酸化其次，HDAC6已被确定为特异性的。 tau 去乙酰化酶允许通过磷酸化修饰 tau。 HDAC6 的抑制应该改变乙酰化/磷酸化的平衡以有利于乙酰化，从而 保护 tau 蛋白免受大脑中的病理性聚集 使用 CSF1R 抑制剂的基本原理是 同样引人注目和强大，因为 rmTBI 导致小胶质细胞激活显着增加， 然后引起星形胶质细胞的二次激活，导致神经元损伤。 消融小胶质细胞，CSF1R 抑制剂应防止小胶质细胞和星形胶质细胞的激活，并减少 CTE 中发生的 CTE 样损伤将在小鼠身上长期研究 rmTBI 的影响。 模拟人类在重复头部后缓慢发展的神经病理学和行为障碍 直到小鼠受到重复的头部撞击以模拟受伤后才会开始治疗。 更密切的临床情况表明，rmTBI 后抑制 HDAC6 或 CSF1R 可以预防或预防。 进一步发现，可以预防 CTE 样 tau 蛋白病理的形成。 这些治疗的 tau蛋白病将减少因高风险而产生的慢性共病。 rmTBI 后的频率包括认知功能障碍、视力和睡眠改变以及抑郁和 该项目与退伍军人管理局的医疗保健任务具有高度的转化相关性。