MT COBRE: CNS GLUTAMATE AND GLUTAMINE TRANSPORT: A MULTIDISCIPLINARY APPROACH

MT COBRE：中枢神经系统谷氨酸和谷氨酰胺转运：多学科方法

• 批准号: 7959447
• 负责人: RICHARD J. BRIDGES
• 金额: $ 22.93万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959447
• 关键词: Address; Biochemistry; Brain; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer Simulation; Funding; Glutamates; Glutamine; Grant; Hippocampus (Brain); Homeostasis; Institution; Membrane Transport Proteins; Modeling; Molecular; Neuraxis; Neuroglia; Neurons; Neurosciences; Pharmacology; Physiological; Physiology; Play; Process; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Synaptic Transmission; Synaptic Vesicles; Synthesis Chemistry; System; Testing; United States National Institutes of Health; excitotoxicity; inhibitor/antagonist; interdisciplinary approach; novel; pharmacophore; reuptake; spatiotemporal

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 is the predominant excitatory transmitter in the central nervous system, and glutamate homeostasis involves the interaction of multiple membrane transporters that are responsible for its packaging into synaptic vesicles (VGLUTs 1-3), its reuptake into glia and neurons (EAATs 1-5), the transfer of its precursor, glutamine, between glia and neurons (presumably involving transport systems A, N, and/or ASC) and its export from glial cells (System Xc; Sxc). There are fundamental unanswered questions concerning many details of this complex system of interacting transport systems. These range from the mechanisms of glutamate and glutamine transport to the roles that each transporter subtype plays in influencing the spatiotemporal profile of synaptically released glutamate and ultimately signaling in the brain. This subproject proposes to organize a multidisciplinary approach involving a team of investigators with expertise in synthetic chemistry, computational modeling, biochemistry, photophysics, and molecular physiology in order to comprehensively address these questions. The specific aims are: 1. To elucidate the molecular pharmacology of the EAAT, VGLUT, Sxc and glutamine transport systems by identifying and characterizing the structural determinants involved in substrate selectivity and pore access in order to develop novel selective inhibitors. 2. To characterize the structural mechanisms of the transporters and test the novel pharmacophore model-derived compounds. 3. To characterize the roles of various transporters in physiological (hippocampal inhibitory and excitatory synaptic transmission) and pathophysiological (hippocampal excitotoxicity) processes.

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。子项目和 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。 谷氨酸是中枢神经系统中主要的兴奋性递质，谷氨酸稳态涉及多个膜转运蛋白的相互作用，这些转运蛋白负责将其包装成突触小泡（VGLUT 1-3），将其重新摄取到神经胶质细胞和神经元（EAAT 1-5）中，将其前体谷氨酰胺在神经胶质细胞和神经元之间转移（可能涉及转运系统A， N 和/或 ASC）及其从神经胶质细胞（系统 Xc；Sxc）的输出。 关于这个相互作用的运输系统的复杂系统的许多细节，还有一些基本的未解答的问题。 这些范围从谷氨酸和谷氨酰胺转运的机制到每种转运蛋白亚型在影响突触释放的谷氨酸的时空分布以及最终在大脑中的信号传导中所发挥的作用。 该子项目建议组织一个多学科方法，由具有合成化学、计算模型、生物化学、光物理学和分子生理学专业知识的研究人员组成的团队参与，以全面解决这些问题。 具体目标是： 1. 通过识别和表征涉及底物选择性和孔通路的结构决定因素，阐明 EAAT、VGLUT、Sxc 和谷氨酰胺转运系统的分子药理学，以开发新型选择性抑制剂。 2. 表征转运蛋白的结构机制并测试新型药效团模型衍生化合物。 3. 表征各种转运蛋白在生理（海马抑制性和兴奋性突触传递）和病理生理（海马兴奋性毒性）过程中的作用。