Role of Neuronal p38 MAPK after Repetitive Mild TBI

项目总结 轻度创伤性脑损伤(MTBI)每年影响数百万人，导致10%-40%的患者长期(&gt；1 1个月)有效治疗策略的生理、情绪、心理和认知症状 都是缺乏的。此外，重复性mTBI(RmTBI)可导致累积的不良反应严重程度和持续时间。 后果。临床和临床前研究表明，神经后遗症的谱系 仅靠生物力学冲击力不能解释损伤后的情况。潜在的损伤机制 反复轻度创伤性脑损伤(RmTBI)后的神经症状尚不清楚，可能是 有别于更严重的脑损伤形式。伍德博士和巴克利博士(共同PI)最近一起工作 发现神经元p38MAPK磷酸化在预测为 RmTBI后认知功能较差。P38MAPK是一条应激反应通路，具有成熟的前体信号通路。 颅脑损伤后小胶质细胞的炎症作用。然而，人们对神经元p38的作用知之甚少。 MAPK磷酸化在调节细胞和认知功能障碍的损伤反应中的作用 在TBI之后。我们的总体假设是p38MAPK的磷酸化，特别是在神经元内，驱动两者1) 细胞因子表达、小胶质细胞激活和脑血流的急性变化和2)慢性变化 小胶质细胞与rmTBI后认知功能障碍对神经元磷酸化信号的作用了解有限 在推动脑外伤后神经炎性、认知和生理变化的过程中，这项提议的目标是 扩大我们对p38 MAPK磷酸化在反复轻度脑损伤后遗症中作用的认识 TBI。因此，研究小组设计了具体的目标：(目标1)定义神经元p38 MAPK的作用 在推动rmTBI后神经炎症中的作用，包括细胞因子表达和小胶质细胞表型；(目标2) 确定神经元p38MAPK在损伤后12周内驱动长期认知结果中的作用 检测短暂性药物抑制p38MAPK保护认知功能的能力，并确定 小胶质细胞是否介导神经元p38MAPK对认知结果的影响；(目标3)确定神经元是否 P38MAPK或神经表达的血管调节细胞因子(IL-17)可推动重复脑血流动力学改变 轻微的脑外伤。拟议的工作将由一个在神经免疫系统分析方面具有专业知识的团队完成。 信号(Wood)，创伤性脑损伤的临床前模型和脑血流量的测量(Buckley)，小胶质细胞 表型(Rangaraju)和脑血流调节机制(Jo)。完成这些目标将 对神经元磷酸信号在驱动重复发作后遗症中的作用进行了前所未有的深入研究 轻微的脑外伤。此外，由于这项工作将测试一种与翻译相关的抑制p38MAPK的药物，成功 这些目标中的一项将提供一种快速可翻译的方法来治疗反复轻度脑外伤。

PROJECT SUMMARY Mild traumatic brain injuries (mTBIs) affect millions per year, leaving 10-40% of patients with long-lasting (>1 month) physical, emotional, psychological, and cognitive symptoms for which effective therapeutic strategies are lacking. Moreover, repetitive mTBI (rmTBI) can lead to cumulative severity and duration of adverse consequences. Clinical and preclinical studies have shown that the spectrum of neurological sequelae seen post-injury cannot be explained by biomechanical impact forces alone. Injury mechanisms underlying neurological symptoms after repetitive mild traumatic brain injury (rmTBI) are poorly understood and may be distinct from more severe forms of TBI. Working together, Drs. Wood and Buckley (co-PIs) have recently discovered that neuronal p38 MAPK phosphorylation is acutely up-regulated in mice predicted to have worse cognitive outcomes after rmTBI. p38 MAPK is a stress-response pathway with a well-established pro- inflammatory role in microglia after TBI. However, there is a gap in knowledge on the role of neuronal p38 MAPK phosphorylation in regulating response to injury that leads to cellular and cognitive dysfunction after TBI. Our overall hypothesis is that p38 MAPK phosphorylation, especially within neurons, drives both 1) acute changes in cytokine expression, microglia activation, and cerebral blood flow and 2) chronic changes in microglia and cognitive deficits after rmTBI. Given limited knowledge on the role of neuronal phospho-signaling in driving these neuroinflammatory, cognitive, and physiologic changes after TBI, the goal of this proposal is to expand our knowledge on the role of p38 MAPK phosphorylation on brain sequalae following repetitive mild TBI. Thus, the investigative team has designed specific aims to: (Aim 1) define the role of neuronal p38 MAPK in driving neuroinflammation after rmTBI, including cytokine expression and microglial phenotype; (Aim 2) define the role of neuronal p38 MAPK in driving longer term cognitive outcomes up to 12 weeks post injury, test the ability of transient pharmacologic inhibition of p38 MAPK to protect cognitive outcomes, and determine if microglia mediate the effects of neuronal p38 MAPK on cognitive outcomes; (Aim 3) determine if neuronal p38 MAPK or a neuronally expressed vasomodulatory cytokine (IL-17) drive changes in CBF after repetitive mild TBI. The proposed work will be completed by a team with expertise in systems analysis of neural immune signaling (Wood), pre-clinical models of traumatic brain injury and measurement of CBF (Buckley), microglial phenotyping (Rangaraju) and mechanisms of cerebral blood flow regulation (Jo). Completion of these aims will yield unprecedented insight into the role of neuronal phospho-signaling in driving sequalae following repetitive mild TBI. Moreover, since this work will test a translationally relevant drug for inhibition of p38 MAPK, success of these aims will present a rapidly translatable approach to treatment of repetitive mild TBI.