Superoxide Radicals in Seizure-Induced Neuronal Death

超氧自由基在癫痫发作引起的神经元死亡中的作用

基本信息

批准号：
7873124
负责人：
MANISHA N PATEL
金额：
$ 9.93万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7873124
关键词：
Aconitate Hydratase Address Animals Antioxidants Area Bioenergetics Brain Injuries Cell physiology Cells Cessation of life Chelating Agents Citric Acid Cycle Clinical Management Confocal Microscopy DNA Data Deoxyguanosine Development Elements Enzymes Epilepsy Event Extracellular Space Ferritin Free Radicals Functional disorder Gene Expression Glutathione Glutathione Disulfide Goals Grant High Pressure Liquid Chromatography Homeostasis Human Hydrogen Peroxide Hydroxyl Radical Iron Iron Chelating Agents Iron Overload Knockout Mice Laboratories Lipid Peroxidation Lipids Mass Spectrum Analysis Measures Mediating Metabolism Metalloporphyrins Mitochondria Mitochondrial DNA Molecular Mus Neuronal Injury Neurons Oxidants Oxidative Stress Participant Process Production Proteins Reaction Regulation Research Personnel Role Seizures Small Interfering RNA Source Status Epilepticus Sulfur Superoxides Techniques Tissues Toxic effect Transferrin Receptor Transgenic Organisms Work base human SOD2 protein indexing liquid chromatography mass spectrometry mitochondrial dysfunction neurotoxicity novel novel therapeutic intervention novel therapeutics overexpression oxidation oxidative damage prevent programs tool

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the mechanisms by which oxidative stress contributes to seizure-induced neuronal death. Neuronal death is a major devastating consequence of status epilepticus. The mechanisms of seizure-induced brain damage remain obscure. Understanding these mechanisms in molecular terms may provide novel therapeutic approaches Aimed at preventing seizure-induced neuronal death. Work in this laboratory has demonstrated that seizure activity results in increased mitochondrial superoxide (CV) production. The goal of this proposal is to determine mechanism by which mitochondrial O2- mediates seizure-induced neuronal death. It is hypothesized that seizure-induced neuronal injury results in part from oxidative inactivation of mitochondrial, aconitase. One important mechanism of O2- toxicity is based on its direct oxidation and resultant inactivation of ironsulfur (Fe-S) proteins such as aconitases and thereby act as a precursor of more potent oxidants e.g. hydroxyl radical. Additionally, the role of mitochondrial aconitase in the tricarboxylic acid cycle can have a major impact on mitochondrial bioenergetics and metabolism. Seizure-induced posttranslational inactivation of mitochondrial aconitase is predicted to contribute to altered mitochondrial iron homeostasis, increased free radical burden and/or a bioenergetic deficit. Specific Aim 1 will determine the consequences of seizure-induced oxidative inactivation of mitochondrial aconitase. Specific Aim 2 will examine if mitochondrial aconitase inactivation and consequent release of iron and hydrogen peroxide imposes a free radical burden and neurotoxicity. Specific Aim 3 will determine if modulation mitochondrial O2~ with catalytic antioxidants and superoxide dismutase-2 influences seizure-induced neuronal death. Whole animal studies will be combined with a diversity of tools and techniques that include high performance liquid chromatography, mass spectrometry, confocal microscopy and transgenic/knockout mice. These studies can identify the precise oxidative events initiated by prolonged seizure activity and suggest novel therapeutic strategies for rescuing neurons in the context of status epilepticus in humans.

描述（由申请人提供）：该提案的长期目标是了解氧化应激导致癫痫引起的神经元死亡的机制。神经元死亡是癫痫持续状态的主要破坏性后果。癫痫引起的脑损伤的机制仍不清楚。从分子角度理解这些机制可能会提供新的治疗方法，旨在预防癫痫引起的神经元死亡。该实验室的工作表明，癫痫发作活动会导致线粒体超氧化物 (CV) 产生增加。该提案的目标是确定线粒体 O2- 介导癫痫引起的神经元死亡的机制。据推测，癫痫发作引起的神经元损伤部分是由于线粒体乌头酸酶的氧化失活所致。 O2-毒性的一个重要机制是基于其直接氧化和由此导致的铁硫 (Fe-S) 蛋白（例如乌头酸酶）的失活，从而充当更有效的氧化剂（例如乌头酸酶）的前体。羟基自由基。此外，线粒体乌头酸酶在三羧酸循环中的作用可以对线粒体生物能学和代谢产生重大影响。癫痫发作引起的线粒体乌头酸酶翻译后失活预计会导致线粒体铁稳态改变、自由基负担增加和/或生物能缺陷。具体目标 1 将确定癫痫引起的线粒体乌头酸酶氧化失活的后果。具体目标 2 将检查线粒体乌头酸酶失活以及随后释放的铁和过氧化氢是否会造成自由基负担和神经毒性。具体目标 3 将确定用催化抗氧化剂和超氧化物歧化酶 2 调节线粒体 O2~ 是否会影响癫痫引起的神经元死亡。整体动物研究将与多种工具和技术相结合，包括高效液相色谱法、质谱法、共聚焦显微镜和转基因/基因敲除小鼠。这些研究可以确定由长期癫痫活动引发的精确氧化事件，并提出在人类癫痫持续状态下拯救神经元的新治疗策略。