Novel therapeutics for chronic effects of repetitive mild TBI

创伤性脑损伤（TBI），通常被称为“沉默的流行病”，在美国被广泛讨论。 今天的新闻。在伊拉克和阿富汗受伤的幸存士兵中，创伤性脑损伤占 伤亡比例（> 22%）高于美国最近的其他战争，如越南战争（12-14%） 战斗伤亡），由于改进的防弹衣和野战医疗。TBI占很大比例 急性和长期战斗伤员护理负担的比例。军方损失了数千名 多年的经验，以及每年数亿美元的培训和教育， TBI对士兵的影响，包括那些过早返回现役的士兵以及士兵 他们无法重返岗位，给退伍军人管理局的医疗保健系统增加了沉重的负担。 许多年轻人在TBI后再也没有恢复病前的技能或责任， 为他们进行全面的康复工作。创伤性脑损伤的后遗症是一个混合的认知 精神和情绪（精神病）的迹象和症状，以及情绪和心理 患者和护理人员的负担可能是巨大的。重复性轻度TBI（r-mTBI）是最常见的TBI之一。 目前冲突的破坏性后果，对晚年健康的影响只是现在 开始出现。人类TBI病因学的多样性给开发和治疗带来了问题。 新疗法的测试，因为通常患者不会寻求治疗， 受伤的时间。因此，TBI发病机制的负面后遗症通常已经很好了。 在寻求干预的时候正在进行。 显然需要在实验室中改进和增加mTBI的建模， 能够解剖和评估TBI依赖性分子反应， 更好的方法来减轻负面结果。我们开发了几种不同的鼠标 重复轻度TBI模型，具有不同的神经行为，神经病理和生化 结果。它们概括了人TBI的特征，因此与翻译相关。 平台我们的假设是，在多个患者中，治疗开始时间较晚的治疗显示出疗效， 不同的r-mTBI模型在人体试验中将具有最大的成功可能性。我们将重点关注两个 我们有很多经验的潜在治疗方法;它们显示出对 TBI发病机制，如神经炎症和tau病理，并且在小鼠中也是有效的 阿尔茨海默病的模型，其中患有r-mTBI的个体的风险增加。 我们将在最后一次损伤或假手术后3个月开始给予这些化合物 已接受手术，并继续进行3个月的认知神经学测试， 在给药期结束时实施安乐死前的行为和运动功能。的影响 每种治疗将进一步评估神经病理学和生化结果，我们将 对每种治疗恢复每种结果的正常（假）表型的能力进行排名。我们 还提出了解剖的脑区域的最新蛋白质组学和脂质组学分析，以充分 描述对损伤和治疗的反应。我们将能够揭示特定的分子 TBI药物发现的治疗靶点，基于独特和重叠的概况 以及与结果测量的相关性。我们有经验， 靶向药物发现的各个方面，这项工作将确定新的治疗途径， r-mTBI研究领域走向合理化，临床前验证治疗的临床试验。这将 特别是对于长期护理至关重要，因为治疗应阻断继发性 TBI后遗症，导致随着时间的推移出现许多毁灭性的临床表现。

Traumatic brain injury (TBI), often referred to as the “silent epidemic,” is widely discussed in the news today. Among surviving soldiers wounded in Iraq and Afghanistan, TBI accounts for a larger proportion of casualties (> 22%) than in other recent US wars, such as Vietnam (12-14% of all combat casualties), due to improved body armor and field medicine. TBI accounts for a large proportion of the acute and long-term combat casualty care burden. The military loses thousands of man-years in experience, and hundreds of millions of training and education dollars each year due to the effects of TBI in soldiers, including those prematurely returned to active duty as well as soldiers who cannot return to service and add to the already heavy burden on the VA healthcare system. Many young adults never regain premorbid skills or responsibilities after TBI despite intensive and comprehensive rehabilitation efforts on their behalf. The sequelae of TBI are a mixture of cognitive psychomotor and emotional (psychiatric) signs and symptoms, and the emotional and psychological burden on patients and caregivers can be enormous. Repetitive mild TBI (r-mTBI) is one of the most devastating outcomes of the current conflicts, with the consequences to later life health only now beginning to emerge. The diversity of etiology of human TBI poses problems for development and testing of new therapeutics, as does the fact that typically patients will not have sought treatment at the time of injury. Thus the negative sequelae of TBI pathogenesis will often already be well underway by the time interventions are sought. There is a clear need for improved and increased modeling of mTBI in the laboratory, to enable the dissection and evaluation of TBI-dependent molecular responses and identification of better approaches to mitigate the negative outcomes. We have developed several different mouse models of repetitive mild TBI, with different neurobehavioral, neuropathological and biochemical outcomes. They recapitulate features of human TBI and are thus of relevance to a translational platform. Our hypothesis is that treatments showing efficacy with late treatment initiation in multiple different r-mTBI models will have greatest likelihood of success in human trials. We will focus on two potential therapeutics with which we have a lot of experienc; they show efficacy against elements of TBI pathogenesis such as neuroinflammation and tau pathology, and are also potent in mouse models of Alzheimer’s Disease, for which individuals suffering from r-mTBI are at increased risk. We will administer these compounds beginning 3 months after the final injury or sham procedure has been received, and continuing for 3 months with neurological testing of cognition, behavior and motor function prior to euthanasia at the end of the treatment phase. The effects of each treatment will further be assessed with neuropathological and biochemical outcomes and we will rank the ability of each treatment to recover the normal (sham) phenotype for each outcome. We also propose state of the art proteomic and lipidomic profiling of dissected brain regions, to fully characterize the response to injury and to treatment. We will be able to reveal particular molecular pathways as therapeutic targets for TBI drug discovery, based on the unique and overlapping profiles from the different treatments, and the correlation with outcome measures. We have experience in all aspects of targeted drug discovery, and this work will identify new therapeutic avenues and move the r-mTBI research field towards clinical trials of rationalized, preclinically validated treatments. This will be of key importance particularly for long term care, as the treatments should block the secondary TBI sequelae, which lead to many of the devastating clinical presentations that emerge over time.