p75NTR Ligands for Treament of Traumatic Brain Injury

项目摘要 创伤性脑损伤（TBIs）构成了一个显着的和不断增长的百分比受伤的退伍军人 人口;爆炸、机动车事故和福尔斯坠落的后遗症。TBI也是死亡的主要原因 和残疾在美国的一般人口，特别是在那些40岁以下。大约2%的 患有慢性TBI相关残疾的人口。目前没有有效的保护或 临床上可用的恢复疗法。在几种CNS创伤模型中， 神经营养因子（例如BDNF、NGF）急性保护组织并促进长期恢复。然而，在这方面， 神经营养素是不良药物，因为它们是不稳定的，表现出差的CNS渗透性，并可增加细胞 死亡和疼痛的路径。这些特性是由于它们的多肽组成和刺激 通过激活多个受体的交叉信号通路。这些问题可能是 通过使用最近发现的小的、稳定的、非肽类药物至少部分地避免了 通过选择性相互作用有效促进神经元存活的化合物（命名为LM 11 A） 与神经营养因子受体p75 NTR，抑制proNGF诱导的死亡，并促进神经祖细胞 增殖p75 NTR和proNGF与几种神经变性过程有关， 包括脊髓中的少突胶质细胞和脊髓中的皮质脊髓束神经元的凋亡性死亡。 脑外伤后。我们假设LM 11 A化合物将抑制细胞死亡发生数小时， 到创伤性损伤后的几天，并且进一步地，对神经发生和神经突可塑性的影响将 在远离损伤的时间（数周，数月）改善大脑结构和功能。另外我们 假设这些作用将与促进存活和分化相关， 信号传导（例如通过AKT、ERK、NF B途径），以及抑制死亡信号传导 (e.g.通过JNK激活）。这项建议的具体目标是：1）检查细胞信号传导的变化 与p75 NTR导向的化合物（LM 11 A-31）抑制细胞死亡相关的 2）确定局灶性脑创伤模型对LM 11 A-31的反应， 早期/延迟期和晚期/慢性期，以及3）确定p75 NTR在以下过程中的作用： 损伤为了实现这些目标，将使用小鼠脑创伤的受控皮质撞击（CCI）模型 为了评估LM 11 A-31对细胞存活和信号传导、神经元和神经胶质细胞生成、胆碱能神经元和神经胶质细胞生成的影响， 神经突密度、“抑郁”（Porsolt强迫游泳试验）和记忆（Morris水迷宫） 在损伤后立即、长达24小时或开始2周治疗的动物中的行为。进一步 研究p75 NTR功能和复合机制在TBI，细胞死亡，过程营养不良和 将在经历CCI的p75 NTR缺陷动物中评价神经发生。这些研究将提供 对于这些或相关化合物最终应用于临床头部创伤的重要信息， 并将促进我们对p75 NTR在病理状态中的作用的认识。这个项目的总体目标是 研究的目的是促进这些神经营养化合物在脑外伤治疗中的应用 和其他条件。

Project Summary Traumatic brain injuries (TBIs) constitute a significant and growing percentage of injuries in the veteran population; sequelae of explosions, motor vehicle accidents and falls. TBI is also a major cause of death and disability in the general population of the US, particularly in those under 40. Approximately 2% of the population is living with a chronic TBI-related disability. There are currently no effective protective or restorative therapies available clinically. In several models of CNS trauma, administration of a neurotrophin (e.g. BDNF, NGF) protects tissues acutely and promotes longer term recovery. However, the neurotrophins are poor drugs as they are labile, exhibit poor CNS penetration and may augment cell death and pain pathways. These properties are due to their polypeptide composition and the stimulation of intersecting signalling pathways through the activation of multiple receptors. These problems may be at least partially circumvented through the use of recently discovered small, stable, non-peptidyl drug-like compounds (designated LM11A) that potently promote neuronal survival through selective interactions with the neurotrophin receptor p75NTR, inhibit proNGF-induced death, and promote neural progenitor cell proliferation. p75NTR and proNGF have been implicated in several neurodegenerative processes, including the apoptotic death of oligodendrocytes in the spinal cord and corticospinal tract neurons in the brain following trauma. We hypothesize that the LM11A compounds will inhibit cell death occurring hours to days following a traumatic injury, and further, that effects on neurogenesis and neurite plasticity will improve brain structure and function at times remote (weeks, months) from the injury. In addition, we postulate that these effects will occur in association with the promotion of survival and differentiative signaling (e.g. via AKT, ERK, NF¿B pathways) by the compound, and the suppression of death signaling (e.g. via JNK activation). The specific aims of this proposal are to: 1) to examine changes in cell signaling associated with the inhibition of cell death by a p75NTR-directed compound (LM11A-31) in the context of focal brain trauma, 2) to determine the responses of a model of focal brain trauma to LM11A-31 given in an early/delayed fashion, and in the late/chronic phase, and 3) to determine the roles of p75NTR following injury. Towards these aims, a controlled cortical impact (CCI) model of brain trauma in mice will be used to assess the effects of the LM11A-31 on cell survival and signalling, neuro- and gliogenesis, cholinergic neurite density, and 'depressive' (Porsolt Forced Swim Test) and memory (Morris Water Maze) behaviors in animals treated immediately, up to 24 hrs, or beginning 2 weeks following injury. To further examine p75NTR function and compound mechanisms in TBI, cell death, process dystrophy and neurogenesis will be evaluated in p75NTR deficient animals subjected to CCI. These studies will provide information important for the eventual application of these or related compounds to clinical head trauma, and will advance our knowledge of the roles of p75NTR in pathologic states. The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions.