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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 谷氨酸是中枢神经系统的主要兴奋性递质，谷氨酸的稳态涉及多个膜转运体的相互作用，这些转运体负责谷氨酸进入突触小泡(VGLUTS 1-3)，它被重新摄取到神经胶质细胞和神经元(EAATs 1-5)，其前体谷氨酰胺在胶质细胞和神经元之间的转移(可能涉及运输系统A、N和/或ASC)以及它从神经胶质细胞输出(系统XC；SXC)。关于这一复杂的相互作用的运输系统的许多细节，还有一些根本的悬而未决的问题。从谷氨酸和谷氨酰胺的转运机制，到每种转运体亚型在影响突触释放的谷氨酸的时空分布，最终在大脑中的信号传递中所扮演的角色。这一分项目建议组织一个涉及合成化学、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小组，以全面解决这些问题。 具体目标是： 1.通过鉴定和表征与底物选择性和孔道进入有关的结构决定因素，阐明EAAT、VGLUT、SXC和谷氨酰胺转运系统的分子药理学，为开发新型选择性抑制剂奠定基础。 2.表征转运蛋白的结构机制，并对新型药效团模型衍生化合物进行验证。 3.研究不同转运蛋白在生理(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。

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.