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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。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，这些转运蛋白负责谷氨酸包装成突触囊泡（VGLUT 1 -3）、谷氨酸再摄取到胶质细胞和神经元（EAAT 1 -5）中以及谷氨酸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）。关于这个复杂的相互作用的运输系统的许多细节，有一些基本的问题没有得到回答。这些范围从谷氨酸和谷氨酰胺转运的机制到每个转运子亚型在影响突触释放的谷氨酸的时空分布和最终在大脑中的信号传导中所起的作用。该子项目建议组织一个多学科的方法，包括一个研究小组，在合成化学，计算建模，生物化学，生物物理学和分子生理学的专业知识，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进入的结构决定因素，阐明EAAT、VGLUT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.描述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。

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.