GLUTAMATE EXCITOTOXICITY

谷氨酸兴奋毒性

• 批准号: 7598522
• 负责人: MARK P MATTSON
• 金额: $ 1.17万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598522
• 关键词: Architecture; Bioenergetics; Cell Death; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Confocal Microscopy; Development; Disruption; Exposure to; Funding; Glutamate Receptor; Glutamates; Grant; Hippocampus (Brain); Institution; Laboratories; Lead; Measures; Mediator of activation protein; Membrane Potentials; Mitochondria; N-Methylaspartate; Neuronal Injury; Neurons; Oxygen; Oxygen Consumption; Pathology; Pharmaceutical Preparations; Population; Post-Traumatic Epilepsy; Production; Pump; Research; Research Personnel; Resources; Source; Stroke; Techniques; Time; Traumatic Brain Injury; United States National Institutes of Health; excitotoxicity; insight; mitochondrial membrane; neuron loss; respiratory; theories

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glutamate excitotoxicity is an important mediator of neuronal cell death and may contribute to the pathology of stroke, epilepsy and traumatic brain injury. The chief mechanism of neuronal injury during prolonged glutamate exposure is due to Ca2+ entry through NMDA glutamate receptors and consequent sequestration of Ca2+ by mitochondria.. This leads to mitochondrial Ca2+ overload, increase in ROS production, disruption of bioenergetics and loss of cellular architecture. Alternative theories suggest that accumulation of Ca2+ and indeed Na+ may lead to an increase in ATP demand from ATP-consuming pumps and consequent depletion of intracellular ATP. It remains a question whether ATP depleting conditions are a determinant or a manifestation of cell death. In conjunction with the Mattson Laboratory (NIA), the BRC has aimed to assess oxygen consumption in single hippocampal neurons in order to gain insight into mitochondrial respiratory capacity during exposure to glutamate. Maximal oxygen consumption is a good indicator of critical ATP depletion, as observed during exposure to mitochondrial uncoupler compounds. Oxygen consumption has only been assessed in whole neuronal populations prior to this proposal. This leads to problems such as the time responsiveness to drugs as well as the need for a homogeneous population of cells. With the development of self-referencing oxygen microsensors, the BRC is able to measure oxygen flux and therefore oxygen consumption at the single cell level. By combining this technique with confocal microscopy, it is anticipated that temporal relationships between mitochondrial membrane potential, intracellular Ca2+ and oxygen consumption will be established and provide clues to the underlying mechanism of excitotoxicity.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 谷氨酸兴奋性毒性是神经元细胞死亡的重要介质，可能导致中风、癫痫和创伤性脑损伤的病理学。长期谷氨酸暴露期间神经元损伤的主要机制是由于 Ca2+ 通过 NMDA 谷氨酸受体进入以及随后线粒体对 Ca2+ 的封存。这导致线粒体 Ca2+ 过载、ROS 产生增加、生物能学破坏和细胞结构丧失。 另一种理论表明，Ca2+ 和 Na+ 的积累可能会导致 ATP 消耗泵对 ATP 的需求增加，从而导致细胞内 ATP 的消耗。 ATP 消耗条件是否是细胞死亡的决定因素或表现仍然是一个问题。 BRC 与马特森实验室 (NIA) 合作，旨在评估单个海马神经元的耗氧量，以便深入了解接触谷氨酸期间的线粒体呼吸能力。正如在暴露于线粒体解偶联剂化合物期间观察到的那样，最大耗氧量是临界 ATP 消耗的良好指标。在此提议之前，仅评估了整个神经元群体的耗氧量。这导致了诸如对药物的时间响应性以及对同质细胞群的需求等问题。随着自参考氧气微传感器的发展，BRC 能够测量氧气通量，从而测量单细胞水平的氧气消耗量。 通过将该技术与共聚焦显微镜相结合，预计将建立线粒体膜电位、细胞内 Ca2+ 和耗氧量之间的时间关系，并为兴奋性毒性的潜在机制提供线索。