MECHANISM OF OLIGODENDROCYTE DEATH IN SPINAL CORD INJURY

少突胶质细胞死亡和脱髓鞘伴随许多CNS损伤， 这些特征在脊髓创伤中特别突出。 白色 物质损伤，包括脱髓鞘，是主要的原因， 脊髓损伤（SCI）后的残疾。尽管临床 这个问题的重要性，细胞和分子机制 导致少突胶质细胞死亡的原因尚不清楚。 以来 少突胶质细胞表达功能性AMPA型谷氨酸受体， 谷氨酸水平升高伴随着SCI，我们计划探索 脊髓少突胶质细胞易受 AMPA/红藻氨酸（KA）受体介导的兴奋性毒性死亡和检测 这种机制是否会导致少突胶质细胞的丢失， 以及脊髓损伤后的脱髓鞘。 我们的初步数据显示 少突胶质细胞在体内外表达功能性AMPA/KA 受体，并被AMPA/KA受体过度激活杀死。 一个 初步表征的发展，生理和 AMPA/KA受体的病理生理学将在纯培养物中完成 从成年啮齿动物脊髓中分离的少突胶质细胞。 我们 体内的初步数据提高了延迟的 和持久的兴奋性毒性可能有助于，部分，延迟 脊髓损伤后少突胶质细胞死亡。 如果得到这些研究的证实，这 将是一个新的和重要的概念在我们的理解 少突胶质细胞死亡的机制， 假设包括非神经元细胞和参与延迟 SCI机制。 超微结构特征和时间模式 脊髓损伤后少突胶质细胞死亡的评估将使用挫伤 和成年啮齿动物的背侧半切损伤。 平行研究使用 将对完整的脑和脊髓进行长期培养 为了研究在缺乏细胞因子的情况下少突胶质细胞死亡的机制， 使体内研究复杂化的因素 我们将进一步研究 少突胶质细胞死亡和脱髓鞘是否减少， 通过旨在改善AMPA/KA的策略改善功能结局 受体兴奋毒性 该项目的最终目标是 通过了解和限制SCI后的功能恢复， 少突胶质细胞死亡和脱髓鞘。

Oligodendrocyte death and demyelination accompany many CNS insults, and these features are particularly prominent in spinal cord trauma. White matter injury, including demyelination, are the major cause of disability after spinal cord injury (SCI). Despite the clinical importance of this problem, the cellular and molecular mechanisms contributing to oligodendrocyte death are unclear. Since oligodendrocytes express functional AMPA-type glutamate receptors and elevated glutamate levels accompany SCI, we plan to explore the possibility that spinal cord oligodendrocytes are vulnerable to AMPA/kainate (KA) receptor-mediated excitotoxic death and examine whether this mechanism may contribute to the loss of oligodendrocytes and demyelination following SCI. Our preliminary data suggest oligodendrocytes, in vitro and in vivo, express functional AMPA/KA receptors, and are killed by AMPA/KA receptor overactivation. An initial characterization of the development, physiology and pathophysiology of AMPA/KA receptors will be completed in pure cultures of oligodendrocytes isolated from adult rodent spinal cord. Our preliminary data in vivo raise the specific possibility that a delayed and protracted excitotoxicity may contribute, in part, to the delayed oligodendrocyte death following SCI. If verified by these studies, this would be a novel and important concept in our understanding of the mechanisms of oligodendrocyte death, extending the excitotoxicity hypothesis to include non-neuronal cells and involvement in delayed mechanisms of SCI. The ultrastructural features and temporal pattern of oligodendrocyte death following SCI will be assessed using contusion and dorsal hemisection injury in adult rodents. Parallel studies using long term culture of intact brain and spinal cord will be carried out to investigate the mechanisms of oligodendrocyte death in the absence of factors complicating in vivo studies. We will further examine whether oligodendrocyte death and demyelination are reduced and the functional outcome improved by strategies designed to ameliorate AMPA/KA receptor excitotoxicity. The ultimate goal of this project is to enhance functional recovery after SCI, by understanding and limiting oligodendrocyte death and demyelination.