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：
8851695
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851695
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 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

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

描述（由申请人提供）：谷氨酸 - 诱导神经元超氧化物生产项目的调节控制摘要/摘要谷氨酸兴奋性兴奋性是脑部创伤中风中细胞死亡的主要原因。超氧化物的神经元产生对于兴奋性细胞死亡是必要的。长期以来，谷氨酸诱导的超氧化物的产生一直被认为是钙涌入和导致的线粒体功能障碍的不可避免的物理后果，但是最近的研究表明，超氧化物是由信号传导酶NADPH氧化酶产生的。在这里，我们旨在描述将神经谷氨酸受体激活与NADPH氧化酶激活联系起来的信号转导途径的关键调节步骤，以及该过程在兴奋性损伤的局部细胞间传播中的作用。初步研究表明，该途径的关键成分包括NR2B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，主导性阴性和遗传方法来评估这些组件的重要性。我们还旨在确定NADPH氧化酶和线粒体在超氧化物产生中可能相互作用的机制。这些研究将使用解离的神经元培养物，脑切片和全动物实验模型进行。这些研究的成功完成将调和该领域的长期矛盾，并将确定有助于急性和慢性神经系统疾病的新型目标和机制。这些研究还将进一步了解神经元之间正常超氧化物信号传导的分子框架，这一过程被认为是调节大脑突触可塑性的过程。 1