GLUTAMATE NEUROTOXICITY IN VITRO

拟议中的实验的目标仍然是描述 谷氨酸神经毒性的细胞机制，这一过程 可能参与了与某些疾病相关的神经元变性 急性或慢性神经系统疾病。此外，独立于直接 疾病的影响，这些机制的阐明可能会产生洞察力 了解神经元损伤的一般性质，从而有助于 神经保护策略的发展。要解析特定的蜂窝 和分子事件，实验将在体外进行，无论是在 原代皮质细胞培养，或在转基因的哺乳动物细胞系中 克隆的谷氨酸受体。以下是三个问题的答案 寻人：L。代谢性谷氨酸受体激活如何影响 兴奋性毒性？2.钙离子内流是否由激活 不同定义的谷氨酸受体可预测随后的兴奋性死亡 即使在非神经细胞中，HEK 293细胞也是如此？3.哪些通路介导晚期 短暂强烈的NMDA受体后钙离子的毒性内流 激活？特别是，NMDA诱导的晚期内向电流 陈和黄所描述的海马神经元，起到了什么作用？ 改进谷氨酸背后的细胞机制的定义 神经毒性可能导致新的治疗手法的发展 被设计用来减轻与几个 疾病状态。此外，这样的定义可能会提供排序 洞察神经细胞损伤的一般问题。并可能因此 对理解人类神经系统疾病具有重要意义。

The goal of the proposed experiments remains the characterization of cellular mechanisms underlying glutamate neurotoxicity, a process which likely participates in the neuronal degeneration associated with certain acute or chronic neurological diseases. Furthermore, independent of direct disease implications, elucidation of these mechanisms may yield insights into the general nature of neuronal injury, and thus aid in the development of neuroprotective strategies. To resolve specific cellular and molecular events, experiments will be carried out in vitro, either in primary cortical cell cultures, or in mammalian cell lines transfected with cloned glutamate receptors. Answers to three questions will be sought: l. How does metabotropic glutamate receptor activation influence excitotoxicity? 2. Does the calcium influx triggered by activation of different defined glutamate receptors predict subsequent excitotoxic death even in non-neuronal, HEK 293 cells? 3. Which pathways mediate the late toxic influx of Ca2+ into neurons that follows brief intense NMDA receptor activation? In particular, does the NMDA-induced late inward current described by Chen and Wong on hippocampal neurons, play a role? Improved definition of the cellular mechanisms underlying glutamate neurotoxicity could lead to the development of new therapeutic maneuvers designed to attenuate the neuronal destruction associated with several disease states. Furthermore, such a definition would likely provide sorted insight into the general problem of neuronal cell injury. and might thus have valuable implications for understanding human neurological illness.