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.

项目摘要/摘要 创伤性脑损伤（TBI）被称为最近军事战斗行动的“签名伤害” 在伊拉克和阿富汗。兵役成员和退伍军人最普遍的TBI形式 是重复的，轻度的TBI或RMTBI。除了头部受伤的直接影响外，rmtbi也有关联 具有许多重要和慢性的合并症，包括认知功能障碍，睡眠障碍， 视觉功能和精神病并发症的改变（例如抑郁，自杀，动画）。 rmtbi及其 合并条件准确对军事人员和退伍军人的钢铁造成钢铁损失，TBI国家的成本是 估计每年为600亿美元。 RMTBI改变脑功能的机制不好 迄今为止，了解TBI的新疗法的所有临床试验都失败了。因此，有效的治疗 因为不存在TBI。 RMTBI最令人震惊的方面也许是重复的轻度影响的可能性 头部不会引起临床意义或可识别的符号，而是引起运动的级联 神经退行性和精神病的终点。该应用的主要目标是1） 并验证RMTBI的人源化小鼠模型和2）测试两种基于机制的新疗法 RMTBI的长期后果。这些目标将通过采用新的RMTBI模型来实现 非常温和，即使在多达20个头部撞击之后，并且不会导致任何行为或神经元 治疗期结束时的病理。我们包括初步数据，显示RMTBI导致 沿白质沿着白质的反应性神经胶质病和感染增加的延迟和进行性出现， 并增加了微管稳定分子Tau的病理形式。此外，这种RMTBI模型 导致慢慢发展认知缺陷和精神病样疾病（例如焦虑和抑郁）， rmtbi治疗过程后，这两个都不是证据。这些神经元和行为 结果是慢性创伤性脑病（CTE）的标志性迹象，在 兵役成员暴露于RMTBI的尸体大脑。将两种新药作为疗法测试 对于RMTBI，包括组蛋白脱乙酰基酶6（HDAC6）的抑制剂和刺激性因子1受体 （CSFR1）抑制剂消除CNS小胶质细胞。使用HDAC6抑制剂治疗的基本原理 rmtbi引人注目的原因有几个。首先，通过乙酰化对tau进行修饰可保护其免受聚集 （即其病理形式）通过抑制其磷酸化。其次，HDAC6已被确定为特定 脱乙酰化tau的酶。 tau的脱乙酰化允许通过磷酸化修饰tau。第三， HDAC6的抑制作用应移动乙酰化/磷酸化的平衡，从而有利于乙酰化，从而有利于 保护tau免受大脑中病理聚集的影响。使用CSF1R抑制剂的基本原理是 同样令人信服和强大，因为rmtbi会导致小胶质细胞激活显着增加 然后引起星形胶质细胞的继发激活。这种增加的神经胶质反应性导致神经元损伤。经过 减轻小胶质细胞，CSF1R抑制剂应防止小胶质细胞和星形胶质细胞激活并减少 CTE中发生类似CTE的损害。 RMTBI的影响将在小鼠的慢性时框架上进行研究 模拟重复头后，人类在人类中看到的缓慢发育的神经病理学和行为障碍 受伤。治疗直到小鼠暴露于重复头部撞击后才能开始治疗以模拟 临床状况更加紧密。假设RMTBI后HDAC6或CSF1R的抑制作用将预防或 减少类似CTE的TAU病理学的发展。进一步假设预防 使用这些治疗方法的tauopathies将减少慢性合并状况高 rmtbi之后的频率包括认知功能障碍，视力和睡眠的改变以及抑郁症和抑郁症 类似焦虑的行为障碍。该项目对VA医疗保健任务具有很高的转化相关性。