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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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，谷氨酸稳态涉及多种膜转运蛋白的相互作用，这些转运蛋白负责将谷氨酸包装到突触囊泡（VGLUT1-3），再摄取到胶质细胞和神经元（EAAT1-5），以及其前体谷氨酰胺在胶质细胞和神经元之间的转移（可能涉及转运系统A、N和/或ASC）。关于这个相互作用的转运体的复杂系统的许多细节，有一些基本的未解之谜。其中包括谷氨酸和谷氨酰胺运输的机制，以及每种转运体亚型在影响突触释放谷氨酸的时空分布并最终在大脑中传递信号方面所起的作用。本子项目拟组织一个由合成化学、计算建模、生物化学、光物理和分子生理学专家组成的多学科研究小组，以全面解决这些问题。具体目标是：1。通过鉴定和表征参与底物选择性和孔通路的结构决定因素，阐明EAAT、VGLUT和谷氨酰胺运输系统的分子药理学，以开发新的选择性抑制剂。2. 表征转运体的结构机制，并测试新型药效团模型衍生化合物。3. 表征各种转运体在生理（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 sysem, and glutamate homeostasis involves the interaction of multiple membrane transporters that are responsible for its packaging into synaptic vesicles (VGLUT1-3), its reuptake into glia and neurons (EAAT1-5), and the transfer of its precursor, glutamine, between glia and neurons (presumably involving transport systems A, N, and/or ASC). There are fundamental unanswered questions concerning many details of this complex system of interacting transporters. 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 signalling 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 pharmacoloyg of the EAAT, VGLUT, and glutamine transport systems by identifying and characterizing the structural determinanats 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.