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

催化氧化还原剂对重复轻度创伤性脑损伤后修复和神经发生的影响

• 批准号: 9190491
• 负责人: Jessica Nicole Nichols
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-29 至 2018-06-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190491
• 关键词: Acceleration; Accounting; Acute; Adult; Aggressive behavior; Animal Model; Anxiety; Behavior; Behavioral; Biochemical; Brain; Brain Concussion; Cell Count; Cognition; Cognitive; Cognitive deficits; Committee Members; Data; Diffuse Axonal Injury; Emotional; Emotions; Enzyme-Linked Immunosorbent Assay; Ethics; Evaluation; Event; Faculty; Feedback; Functional disorder; General Population; Gliosis; Health; Hippocampus (Brain); Histology; Hour; Human; Immunoblotting; Immunofluorescence Immunologic; Impairment; Incidence; Individual; Inflammation; Injury; Intervention; Journals; Label; Length; Literature; Location; Manganese; Measures; Mechanics; Mediating; Mental Depression; Mentorship; Metabolic; Metalloporphyrins; Military Personnel; Modeling; Mus; NF-kappa B; Neuraxis; Neurons; Newborn Infant; Oxidative Stress; Persons; Play; Porphyrins; Pro-Opiomelanocortin; Process; Production; Proliferating; Reactive Oxygen Species; Recovery; Recovery of Function; Role; Scientific Inquiry; Series; Signal Transduction; Sleep; Sports; Techniques; Testing; Therapeutic; Time; Tissue Stains; Tissues; Training; Transgenic Mice; Traumatic Brain Injury; adult neurogenesis; behavior test; clinically relevant; cognitive development; design; enhanced green fluorescent protein; experience; granule cell; improved; male; meetings; mild traumatic brain injury; morris water maze; neurochemistry; neurogenesis; neuroinflammation; neuron loss; neuropsychiatric symptom; neuropsychiatry; newborn neuron; novel; novel therapeutics; outcome forecast; peer; prevent; repaired; research study; therapeutic target; therapy development; transcription factor

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.

项目总结 脑震荡或轻度创伤性脑损伤(MTBI)占所有脑损伤的75%，通常导致认知障碍 和神经精神损害，那些遭受反复MTBI(RmTBI)的人预后更差。这个 绝大多数获得单个mTBI的人在大约1周内恢复，而不需要干预 但rmTBI并非如此。因此，对于改善对自发修复的理解存在着未得到满足的需求 单次mTBI后反复mTBI损害的机制及其治疗发展的需要 减少损伤，促进rmTBI后恢复。此前，我们的实验室和其他实验室已经表明 单次mTBI后神经再生增强；然而，重复mTBI后并未检测到神经再生。 MTBI后出现的神经炎症已被证明可以改变神经发生。其中两个 神经炎症的主要贡献者是核因子-kappaB(NF-κB)和活性氧 (ROS)。有趣的是，我们表征了一种新型的催化氧化还原剂，金属卟啉锰。 (111)-四(N-乙基吡啶-2-基)卟啉(MnTe-2-PyP5+)，既能消散ROS，又能抑制 因此，我们假设同时靶向多个继发性损伤 减轻rmTBI后神经炎症的机制将通过促进 神经发生。为了检验这一想法，我们将1)评估在以下情况下给予MnTE-2-PyP5+的假设 RmTBI通过消散ROS和抑制NF-κB来减少神经炎症和提供组织保护 信号转导；2)验证mTBI后给予MnTE-2-PyP5+有助于减轻rmTBI诱导的假说 认知、情绪和行为方面的缺陷；以及3)评估mTBI后给药的假设 MnTe-2-PyP5+可促进rmTBI后的神经再生。这些目标将使用不同的分析工具来实现 技术包括与临床相关的冲击加速mTBI模型；激活的 核因子-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.免疫荧光分析 选择性标记新生颗粒细胞转基因小鼠的神经发生和形态 对新生神经元的评估。这些实验有望阐明两者之间的相互作用 RmTBI后的神经炎症和神经再生，以及提供一种潜在的治疗方法，可以阻止 继发性损伤级联作用，促进功能恢复。 提议的PI培训计划包括每周参加实验室会议、日记俱乐部和 研讨会。PI还将参加毕业实习生研讨会系列，来自教职员工和 并出席每年一次的国家科学会议。关于道德实践的正式和非正式培训 科学研究将继续进行。此外，国际和平协会将定期与赞助商坎迪斯·弗洛伊德博士会面 每两年与委员会成员进行一次持续的指导。