p75NTR Ligands for Treament of Traumatic Brain Injury

描述（由申请人提供）： 项目摘要：创伤性脑损伤（TBI）在退伍军人人群中构成了显著且不断增长的伤害比例;爆炸、机动车事故和福尔斯的后遗症。TBI也是美国普通人群死亡和残疾的主要原因，特别是40岁以下的人群。大约2%的人口患有与TBI相关的慢性残疾。目前临床上没有有效的保护性或恢复性治疗。在CNS创伤的几种模型中，神经营养因子（例如BDNF、NGF）的施用急性保护组织并促进长期恢复。然而，神经营养因子是差的药物，因为它们不稳定，表现出差的CNS渗透，并且可能增加细胞死亡和疼痛途径。这些特性是由于它们的多肽组成和通过激活多种受体刺激交叉信号通路。这些问题可以通过使用最近发现的小的、稳定的、非肽基药物样化合物（命名为LM 11 A）来至少部分地避免，所述化合物通过与神经营养因子受体p75 NTR的选择性相互作用而有效地促进神经元存活，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，包括创伤后脊髓中少突胶质细胞和脑中皮质脊髓束神经元的凋亡性死亡。我们假设LM 11 A化合物将抑制创伤性损伤后数小时至数天发生的细胞死亡，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）改善脑结构和功能。此外，我们假设这些作用将与化合物促进存活和分化信号传导（例如通过AKT、ERK、NF：B途径）以及抑制死亡信号传导（例如通过JNK活化）相关。这项建议的具体目标是：1）检查与p75 NTR导向的化合物抑制细胞死亡相关的细胞信号传导的变化2）确定局灶性脑创伤模型对以早期/延迟方式和在晚期/慢性期给予的LM 11 A-31的反应，（3）探讨p75 NTR在损伤后的作用。为了这些目的，将使用小鼠脑创伤的受控皮质撞击（CCI）模型来评估LM 11 A-31对损伤后立即、至多24小时或开始2周治疗的动物中的细胞存活和信号传导、神经元和神经胶质生成、胆碱能神经突密度和“抑郁”（Porsolt强迫游泳试验）和记忆（Morris水迷宫）行为的影响。为了进一步研究p75 NTR在TBI中的功能和化合物机制，将在经历CCI的p75 NTR缺陷动物中评价细胞死亡、过程营养不良和神经发生。这些研究将为这些或相关化合物在临床头部创伤中的最终应用提供重要信息，并将促进我们对p75 NTR在病理状态中的作用的认识。这项研究的总体目标是推进这些神经营养化合物在治疗脑创伤和其他疾病中的应用。 公共卫生相关性： 在现代战斗和退伍军人中，由于爆炸、机动车事故和福尔斯跌倒，脑损伤占受伤人数的比例很大，而且可能在不断增加。目前的急性和慢性治疗，如控制脑压和康复训练，效果有限，需要新的药理学和细胞为基础的方法。这项在脑创伤模型中测试一种有前途的新神经细胞存活促进化合物（称为LM 11 A-31）的提议直接解决了这一需求。拟议的实验将确定延迟早期治疗是否有效，以及受伤后很长时间的治疗是否会改善症状。此外，他们还将深入了解该化合物的主要作用是否是由于改善细胞存活，增加再生或两者兼而有之。如果有效的话，用这种类型的化合物治疗可能代表在脑创伤后保护和恢复组织和功能的新疗法开发方面的重要进展。

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. PUBLIC HEALTH RELEVANCE: Narrative Brain injuries constitute a significant and perhaps growing percentage of injuries in modern combat and the veteran population, due to explosions, motor vehicle accidents and falls. Current acute and chronic therapies, such as control of brain pressure and rehabilitation training, have limited effectiveness, and new pharmacologic and cell-based approaches are needed. This proposal, to test a promising new nerve cell-survival-promoting compound (called LM11A-31) in models of brain trauma addresses this need directly. The proposed experiments will determine whether delayed-early treatment is effective, and whether treatment long after the injury will improve symptoms. In addition, they will provide insight into the question of whether the compound's main effects are due to improving cell survival, increasing regeneration or both. If effective, treatment with compounds of this type could represent an important advance in the development of new therapies for preserving and recovering tissue and function following brain trauma.