Disruption of Glutamate Transport by Motor Neuron ROS

运动神经元 ROS 破坏谷氨酸转运

• 批准号: 6487601
• 负责人: SHYAM S RAO
• 金额: $ 2.54万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6487601
• 关键词: amyotrophic lateral sclerosis; cell membrane; fluorescent dye /probe; free radical oxygen; glia; glutamate receptor; glutamate transporter; laboratory mouse; microelectrodes; motor neurons; neural degeneration; oxidative stress; pathologic process; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by selective loss of motor neurons which progresses rapidly to paralysis and death. Findings of decreased glutamate transport/uptake capacity and elevated extracellular glutamate levels in ALS patients suggest a role for glutamate excitotoxicity in the disease. Indeed, elevations in glutamate have been shown experimentally to induce selective Reactive Oxygen Species (ROS) production in motor neurons and a selective motor neuron injury, similar to ALS. A crucial missing link in understanding ALS is the factor responsible for this loss of glutamate transport (mediated primarily by glial cells). As glutamate uptake is ROS sensitive, we propose the following hypothesis: elevated extracellular glutamate selectively induces ROS production in motor neurons which directly inhibits glial glutamate uptake. Exploration of such a novel feed-forward model may elucidate new targets for potential therapeutic intervention. This proposal aims to examine the hypothesis using in vitro cell culture to characterize selective ROS production in motor neurons and whether it is capable of escaping the cell membrane and affecting adjacent glia, using oxidant sensitive fluorescent dyes and oxidative damage markers. Finally, studies in animal models of ALS will assess if these processes can be shown to occur in vivo.

描述(由申请人提供)： 肌萎缩侧索硬化症是一种毁灭性的神经退行性疾病 以运动神经元的选择性丢失为特征的，这种运动神经元迅速进展到 瘫痪和死亡。谷氨酸转运/摄取能力下降的研究结果 ALS患者细胞外谷氨酸水平升高提示 谷氨酸在疾病中的兴奋性毒性。事实上，谷氨酸的含量升高 在实验中被证明可以诱导选择性的活性氧物种(ROS) 运动神经元的产生和选择性运动神经元损伤，类似于 肌萎缩侧索硬化。在理解肌萎缩侧索硬化症方面，一个关键的缺失环节是导致 这种谷氨酸运输的丧失(主要由神经胶质细胞介导)。AS 谷氨酸摄取是ROS敏感的，我们提出了以下假设： 胞外谷氨酸升高选择性诱导运动神经元产生ROS 直接抑制神经胶质细胞谷氨酸摄取的神经元。探索这样一种 新的前馈模型可能阐明潜在治疗的新靶点 干预。这项建议旨在使用体外细胞来检验这一假说。 培养以表征运动神经元中选择性ROS的产生以及 它能够逃脱细胞膜，影响邻近的神经胶质细胞，使用 氧化敏感的荧光染料和氧化损伤标记物。最后， 在ALS动物模型中的研究将评估这些过程是否可以证明 发生在活体内。