Effects of a catalytic oxidoreductant on repair and neurogenesis after repeated mild traumatic brain injury

项目摘要 脑震荡或轻度创伤性脑损伤（mTBI）占所有TBI的75%，并且通常导致认知功能障碍。 和神经精神损害，其中那些持续反复mTBI（rmTBI）的患者预后较差。的 绝大多数获得单次mTBI的个体在没有干预的情况下在大约1周内恢复， 对于rmTBI来说不是这样。因此，对于提高对自发修复的理解存在未满足的需求。 单次mTBI后的机制因重复mTBI而受损，需要开发治疗方法 以减少rmTBI后的损伤并促进恢复。之前，我们的实验室和其他人已经证明， 神经发生在单次mTBI后增强;然而，在重复mTBI后尚未检查到。 mTBI后存在的神经炎症已被证明会改变神经发生。两 神经炎症的主要贡献者是核因子κ B（NF-κB）和活性氧 （ROS）。有趣的是，我们已经确定了一种新的催化氧化还原剂，金属卟啉锰 （111）-四（N-乙基吡啶鎓-2-基）卟啉（MnTE-2-PyP 5+），其既消散ROS又抑制 NF-κB的活化。因此，我们假设同时针对多个继发性损伤 减少rmTBI后神经炎症的机制将通过促进神经损伤减轻缺陷并增强恢复。 神经发生为了测试这个想法，我们将1）评估在施用MnTE-2-PyP 5+之后施用MnTE-2-PyP 5+的假设。 rmTBI将通过消散ROS和抑制NF-κB减轻神经炎症并赋予组织保护 2）测试mTBI后施用MnTE-2-PyP 5+有助于减轻mTBI诱导的细胞凋亡的假设。 认知、情感和行为缺陷;以及3）评估mTBI后施用 MnTE-2-PyP 5+可促进rmTBI后的神经发生。这些目标将通过多种分析方法来实现。 技术，包括临床相关的冲击加速度mTBI模型; NF-κB和氧化应激标志物;神经炎症和组织损伤的组织学评估; 认知、睡眠和神经精神症状的行为评估; 用选择性标记新生颗粒细胞的转基因小鼠的神经发生; 评估新生神经元。这些实验有望阐明 rmTBI后的神经炎症和神经发生，以及提供一种潜在的治疗方法，可以阻止 继发性损伤级联反应，促进功能恢复。 PI的拟议培训计划包括每周参加实验室会议、期刊俱乐部， 研讨会等PI还将参加一系列研究生实习研讨会，指导教师的反馈， 同行和出席国家科学会议，每年。职业道德实践方面的正式和非正式培训 科学研究将继续进行。此外，PI将定期与申办者Candace弗洛伊德博士会面 并每两年与委员会成员继续指导。

PROJECT SUMMARY Concussions or mild traumatic brain injuries (mTBI) account for 75% of all TBIs and often result in cognitive and neuropsychiatric impairment with those sustaining repeated mTBIs (rmTBI) having a worse prognosis. The vast majority of individuals acquiring a single mTBI recover in approximately 1 week without intervention which is not the case for rmTBI. Thus there is an unmet need for improved understanding of the spontaneous repair mechanism after single mTBI that is impaired with repeated mTBI and a need for the development of therapies to reduce damage and promote recovery after rmTBI. Previously, our lab and others have shown that neurogenesis is enhanced after a single mTBI; however, it has not been examined after repeated mTBI. Neuroinflammation, which is present after mTBI, has been demonstrated to alter neurogenesis. Two of the major contributors to neuroinflammation are nuclear factor kappa B (NF-κB) and reactive oxygen species (ROS). Intriguingly, we have characterized a novel catalytic oxidoreductant, the metalloporphyrin manganese (111)-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+), that both dissipates ROS and inhibits the activation of NF-κB. Therefore, we hypothesize that simultaneously targeting multiple secondary injury mechanisms to reduce neuroinflammation after rmTBI will mitigate deficits and enhance recovery by promoting neurogenesis. To test this idea we will 1) Evaluate the hypothesis that administration of MnTE-2-PyP5+ after rmTBI will reduce neuroinflammation and confer tissue protection by dissipating ROS and inhibiting NF-κB signaling; 2) Test the hypothesis that post-mTBI administration of MnTE-2-PyP5+ helps alleviate rmTBI-induced deficits in cognition, emotion, and behavior; and 3) Assess the hypothesis that post-mTBI administration of MnTE-2-PyP5+ will promote neurogenesis after rmTBI. These aims will be achieved using diverse analytical techniques including a clinically-relevant impact-acceleration mTBI model; biochemical analysis of activated NF-κB and markers of oxidative stress; histological assessment of neuroinflammation and tissue damage; behavioral evaluation of cognition, sleep, and neuropsychiatric symptoms; immunofluorescence analysis of neurogenesis in transgenic mice with selectively labelled newborn granule cells; and morphological assessment of newborn neurons. These experiments are expected to elucidate the interaction between neuroinflammation and neurogenesis after rmTBI, as well as offer a potential therapeutic that could halt the secondary injury cascade and promote functional recovery. The proposed training plan for the PI includes weekly participation in lab meetings, journal clubs, and seminars. The PI will also partake in a graduate trainee seminar series with directed feedback from faculty and peers and present at a national scientific meeting, annually. Formal and informal training in ethical practices in scientific inquiry will be continued. Additionally, the PI will meet regularly with the sponsor Dr. Candace Floyd and bi-annually with committee members for continued mentorship.