INFLAMMATORY APOPTOSIS AFTER SPINAL CORD INJURY

描述(改编自申请者摘要)：基本机制 脊髓损伤后延迟性细胞死亡的原因尚不清楚。 继发性损伤被认为是导致进行性细胞死亡和 在最初的身体侮辱后组织丢失。创伤后炎症 反应可能在继发性损伤中起重要作用。红衣主教 急性炎症反应的特征已经在 在遭受创伤性侮辱后，脊髓至少受伤了几天。 中枢神经系统的炎症过程偏向于白质。 白质损害，包括脱髓鞘，是导致 脊髓损伤后的残疾。细胞因子是炎症介质，由 炎性细胞。细胞因子，特别是肿瘤坏死因子-α (肿瘤坏死因子)，已被证明引起少突胶质细胞(ODCs)的凋亡。 体外和体内脱髓鞘。我们将探索可能的致病作用 肿瘤坏死因子-α在创伤后ODC细胞凋亡中的作用 炎症反应。简化方案如下所示： 本项目将主要关注肿瘤坏死因子-α在ODC凋亡中的作用 在SCI之后。体内研究，使用大鼠和转基因小鼠脊髓损伤模型，以及 在体外研究，使用ODC培养，将进行测试 假设肿瘤坏死因子-α的表达至少部分参与了ODC 脊髓损伤后细胞凋亡。我们还将检验这样一种假设，即凋亡的ODC 细胞死亡和随后的脱髓鞘减少，功能结果是 通过有效抑制肿瘤坏死因子-α表达或 阻止其行动。该项目还将作为一个平台 开发新的治疗方案，包括联合策略 针对创伤后炎症级联反应的不同步骤。这个 本项目的最终目标是促进脊髓损伤后的功能恢复 通过减少ODC的死亡。

DESCRIPTION (Adapted from Applicant's Abstract): The underlying mechanism of delayed cell death in the spinal cord after injury is poorly understood. Secondary injury has been proposed to cause progressive cell death and tissue loss after the initial physical insult. Post-traumatic inflammatory reaction may play an important role in the secondary injury. Cardinal features of an acute inflammatory response have been demonstrated in the injured cord for at least several days after the traumatic insult. Inflammatory processes in the CNS have a predilection for the white matter. White matter lesions, including demyelination, are the major cause of disability after SCI. Cytokines are inflammatory mediators expressed by inflammatory cells. Cytokines, particularly tumor necrosis factor-alpha (TNF), have been shown to cause apoptosis in oligodendrocytes (ODCs) in vitro and demyelination in vivo. We will explore a possible pathogenic role of TNF-alpha in ODC apoptosis in the context of a post-traumatic inflammatory reaction. A simplified scheme is shown below: This project will focus mainly on the role of TNF-alpha in ODC apoptosis after SCI. In vivo studies, using rat and transgenic mouse SCI models, and in vitro studies, using ODC cultures, will be conducted to test the hypothesis that TNF-alpha expression contributes, at least partially, to ODC apoptosis after SCI. We will also test the hypothesis that apoptotic ODC cell death and subsequent demyelination is reduced and functional outcome is improved by interventions that effectively inhibit TNF-alpha expression or block its actions. This project will also serve as a platform for developing new therapeutic regimens, including combination strategies directed at different steps in the post-traumatic inflammatory cascade. The ultimate goal of this project is to enhance functional recovery after SCI through a reduction in ODC death.