Regulatory Control of Glutamate - Induced Superoxide Production

谷氨酸诱导的超氧化物产生的调节控制

基本信息

批准号：
8421981
负责人：
RAYMOND A SWANSON
金额：
$ 33.25万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8421981
关键词：
1-Phosphatidylinositol 4-Kinase 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Acute Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Binding Brain Calcium Catalytic Domain Cell Death Cells Cessation of life Chronic Chronic Disease Coupled Coupling Disease Dominant-Negative Mutation Enzymes Experimental Animal Model Genetic Glutamate Receptor Glutamates Injury Intervention Link Mediating Membrane Mitochondria Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate NADPH Oxidase NR2B NMDA receptor Neuroglia Neuronal Injury Neurons Onset of illness Oxidative Stress PDPK1 gene PTEN gene Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase A2 Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Production Protein Kinase Publishing Reactive Oxygen Species Receptor Activation Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Slice Stroke Superoxides Synaptic plasticity Trauma Traumatic Brain Injury Work abstracting atypical protein kinase C base cell injury excitotoxicity human CYBA protein inhibitor/antagonist mitochondrial dysfunction mouse model nerve injury nervous system disorder novel protein kinase C zeta receptor respiratory src-Family Kinases

项目摘要

DESCRIPTION (provided by applicant): Regulatory control of glutamate - induced neuronal superoxide production Project Summary/Abstract Glutamate excitotoxicity is a primary cause of cell death in stroke, brain trauma. Neuronal production of superoxide is necessary for excitotoxic cell death to occur. Glutamate-induced superoxide production has long been considered an inevitable, physical consequence of calcium influx and resulting mitochondrial dysfunction, but recent studies show that the superoxide is instead produced by the signaling enzyme, NADPH oxidase. Here we aim to delineate key regulatory steps in the signal transduction pathway linking neuronal glutamate receptor activation to NADPH oxidase activation, and the role of this process in local cell-to-cell propagation of excitotoxic injury. Preliminary studies suggest that key components of this pathway include the NR2B subunit of NMDA-type glutamate receptors, phosphoinositol-3-kinase (PI3K), PTEN, and phospholipase A2. The studies proposed here will evaluate the importance of each of these components using pharmacological, dominant negative, and genetic approaches. We also aim to identify mechanisms by which NADPH oxidase and mitochondria may interact in superoxide production. These studies will be performed using dissociated neuronal cultures, brain slices, and whole-animal experimental models. Successful completion of these studies will reconcile long-standing contradictions in this field, and will identify novel targets and mechanisms contributing to both acute and chronic neurological disorders. These studies will also further our understanding of the molecular framework for normal superoxide signaling between neurons, a process thought to modulate synaptic plasticity in brain. 1 PUBLIC HEALTH RELEVANCE: Glutamate - induced neuronal death is an important cause of neural injury in both acute-onset disorders such as stroke and trauma, and more chronic disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. The reactive oxygen species, superoxide, is known to mediate glutamate-induced neuronal death. Studies proposed here will identify key steps leading from glutamate receptor activation to the production of superoxide, and thereby identify ways of blocking or modulating this important cell injury pathway.

描述（由申请人提供）：谷氨酸诱导的神经元超氧化物产生的调节控制项目摘要/摘要谷氨酸兴奋性毒性是中风、脑外伤中细胞死亡的主要原因。神经元产生超氧化物是兴奋性毒性细胞死亡发生所必需的。长期以来，谷氨酸诱导的超氧化物产生一直被认为是钙流入和由此导致的线粒体功能障碍不可避免的物理后果，但最近的研究表明，超氧化物是由信号酶 NADPH 氧化酶产生的。在这里，我们的目的是描绘连接神经元谷氨酸受体激活与 NADPH 氧化酶激活的信号转导途径中的关键调控步骤，以及该过程在兴奋性毒性损伤的局部细胞间传播中的作用。初步研究表明，该通路的关键成分包括 NMDA 型谷氨酸受体的 NR2B 亚基、磷酸肌醇 3 激酶 (PI3K)、PTEN 和磷脂酶 A2。这里提出的研究将使用药理学、显性失活和遗传方法来评估每个成分的重要性。我们还旨在确定 NADPH 氧化酶和线粒体在超氧化物产生中相互作用的机制。这些研究将使用分离的神经元培养物、脑切片和整体动物实验模型进行。这些研究的成功完成将解决该领域长期存在的矛盾，并将确定导致急性和慢性神经系统疾病的新靶点和机制。这些研究还将进一步加深我们对神经元之间正常超氧化物信号传导的分子框架的理解，这一过程被认为可以调节大脑的突触可塑性。 1 公共健康相关性：谷氨酸诱导的神经元死亡是中风和创伤等急性发作性疾病以及肌萎缩侧索硬化症和阿尔茨海默氏病等慢性疾病中神经损伤的重要原因。已知活性氧、超氧化物可以介导谷氨酸诱导的神经元死亡。这里提出的研究将确定从谷氨酸受体激活到超氧化物产生的关键步骤，从而确定阻断或调节这一重要细胞损伤途径的方法。