p75NTR Ligands for Treament of Traumatic Brain Injury

描述(由申请人提供)： 项目概述：在退伍军人中，创伤性脑损伤(TBI)占伤害的比例越来越大；爆炸、机动车事故和跌倒的后遗症。脑外伤也是美国总人口死亡和残疾的主要原因，特别是在40岁以下的人群中。大约2%的人口患有慢性创伤性脑损伤相关残疾。目前临床上还没有有效的保护性或恢复性疗法。在几种中枢神经系统创伤模型中，应用神经营养因子(如BDNF、NGF)可以有效地保护组织并促进长期恢复。然而，神经营养因子是劣质药物，因为它们不稳定，表现出较差的中枢神经系统穿透性，并可能增加细胞死亡和疼痛通路。这些特性是由于它们的多肽组成和通过激活多个受体刺激交叉的信号通路。这些问题至少可以通过使用最近发现的小的、稳定的非肽类药物化合物(命名为LM11A)来部分绕过，这些化合物通过与神经营养素受体p75NTR的选择性相互作用而有效地促进神经元存活，抑制前NGF诱导的死亡，并促进神经前体细胞的增殖。P75NTR和proNGF参与了多种神经退行性变过程，包括创伤后脊髓少突胶质细胞和脑皮质脊髓束神经元的凋亡性死亡。我们假设LM11A化合物将抑制创伤后数小时至数天发生的细胞死亡，此外，对神经发生和轴突可塑性的影响将在远离损伤的时候(几周、几个月)改善大脑结构和功能。此外，我们推测，这些作用与化合物促进生存和分化信号(例如，通过AKT、ERK、NF：B通路)和抑制死亡信号(例如，通过JNK激活)有关。这项建议的具体目的是：1)在局灶性脑创伤的背景下，研究与p75NTR导向的化合物(LM11A-31)抑制细胞死亡相关的细胞信号的变化；2)确定局灶性脑创伤模型对LM11A-31早期/延迟给药和晚期/慢性期的反应；以及3)确定p75NTR在损伤后的作用。为达到这些目标，我们将利用受控皮质冲击(CCI)小鼠脑创伤模型来评估LM11A-31对细胞存活和信号、神经和神经胶质形成、胆碱能神经突起密度、以及创伤后即刻、长达24小时或开始治疗2周的动物的‘抑郁’(Porsolt强迫游泳测试)和记忆(Morris水迷宫)行为的影响。为了进一步研究p75NTR在脑损伤中的作用和复合机制，我们将对CCI后p75NTR缺陷动物的细胞死亡、突起营养不良和神经再生进行评估。这些研究将为这些或相关化合物在临床脑创伤中的最终应用提供重要信息，并将促进我们对p75NTR在病理状态中的作用的了解。这项研究的总体目标是推进这些神经营养化合物在脑创伤和其他疾病治疗中的应用。

DESCRIPTION (provided by applicant): 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.