Regulatory Control of Glutamate - Induced Superoxide Production [Admin Supplement]

谷氨酸诱导的超氧化物产生的监管控制[管理补充]

• 批准号: 8992559
• 负责人: RAYMOND A SWANSON
• 金额: $ 10万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992559
• 关键词: 1-Phosphatidylinositol 4-Kinase; 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Acute; Alzheimer' 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; 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; genetic approach; human CYBA protein; inhibitor/antagonist; mitochondrial dysfunction; mouse model; nerve injury; nervous system disorder; novel; protein kinase C zeta; receptor; respiratory; src-Family Kinases

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

项目摘要/摘要谷氨酸兴奋性毒性是脑卒中、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的必要条件。谷氨酸诱导的超氧化物产生一直被认为是钙流入和线粒体功能障碍不可避免的生理后果，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，我们的目标是描述连接神经元谷氨酸受体激活和NADPH氧化酶激活的信号转导途径中的关键调控步骤，以及这一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，该通路的关键组分包括nmda型谷氨酸受体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、显性阴性和遗传方法评估这些成分的重要性。我们还旨在确定NADPH氧化酶和线粒体可能在超氧化物生产中相互作用的机制。这些研究将使用分离的神经元培养，脑切片和全动物实验模型进行。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。这些研究也将进一步加深我们对神经元之间正常超氧化物信号的分子框架的理解，这一过程被认为是调节大脑突触可塑性的过程。1