OLIGODENDROCYTE DEATH IN CEREBRAL ISCHEMIA

描述 CNS脱髓鞘和少突胶质细胞死亡可能是重要的 许多急性神经系统疾病的功能限制性后遗症，包括 白色物质中风、全脑缺血、脑和脊髓创伤，以及 新生儿脑室周围白质软化症。 然而，细胞机制导致 对缺血性少突胶质细胞损伤的影响最近才被研究。 有毒 谷氨酸受体激活有助于缺氧缺血性神经元 损伤，虽然少突胶质细胞也表达谷氨酸受体， 尚不清楚类似的机制是否会导致少突胶质细胞死亡。 这项提议检验了少突胶质细胞是 易受AMPA受体过度激活介导的兴奋性毒性影响， 这种脆弱性会导致脑损伤， 缺血 研究人员研究了神经胶质细胞培养物中的损伤， 小鼠大脑半球，由少突胶质细胞组成， 星形胶质细胞单层促进少突胶质细胞存活和分化。 在这个模型中，分化的少突胶质细胞表达AMPA受体， 在功能上与钙进入偶联，并被选择性地杀死， 暴露于低微摩尔浓度的选择性AMPA受体 激动剂 建议使用细胞培养和体内模型来检查 AMPA受体介导的缺血性少突胶质细胞死亡。 拟议 研究将确定少突胶质细胞的受体药理学 兴奋性毒性，检查损伤的细胞机制，并评估 预计会减弱少突胶质细胞死亡的药物。 最后，研究 将评估AMPA毒性在缺氧缺血性损伤中的作用， 在细胞培养物和小鼠中风模型中的少突胶质细胞。 的目标 这些研究是为了确定减少 中风和其他疾病期间的白色物质损伤， 少突胶质细胞丢失。

DESCRIPTION CNS demyelination and oligodendrocyte death may be important function-limiting sequelae of many acute neurologic disorders including white matter stroke, global ischemia, brain and spinal cord trauma, and neonatal periventricular leukomalacia. However, cellular mechanisms leading to ischemic oligodendrocyte injury have only recently been explored. Toxic glutamate receptor activation contributes to hypoxic-ischemic neuronal injury, and while oligodendrocytes also express glutamate receptors, it is not known whether similar mechanisms can lead to oligodendrocyte death. This proposal examines the novel hypothesis that oligodendrocytes are vulnerable to excitotoxicity mediated by AMPA receptor overactivation, and that this vulnerability contributes to brain injury during cerebral ischemia. The investigators have studied injury in glial cell cultures from mouse cerebral hemispheres, consisting of oligodendrocytes maintained on an astrocyte monolayer to promote oligodendrocyte survival and differentiation. In this model, differentiated oligodendrocytes express AMPA receptors functionally coupled to calcium entry, and are selectively killed by exposure to low micromolar concentrations of selective AMPA receptor agonists. It is proposed to use cell culture and in vivo models to examine AMPA receptor-mediated ischemic oligodendrocyte dell death. The proposed research will determine the receptor pharmacology of oligodendrocyte excitotoxicity, examine cellular mechanisms of injury, and assess effects of agents predicted to attenuate oligodendrocyte death. Finally, the studies will assess the contribution of AMPA toxicity in hypoxic-ischemic injury of oligodendrocytes in cell culture and in mouse stroke models. The goal of these studies is to identify pharmacological approaches to reduction of white matter injury during stroke and other disorders characterized by oligodendrocyte loss.