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

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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(VGLUT1-3)，它被重新摄取到胶质细胞和神经元(EAAT1-5)，以及它的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)。关于这个复杂的相互作用的运输者系统的许多细节，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一种转运体亚型在影响突触释放的谷氨酸的时空分布以及最终大脑中的信号传递方面所起的作用，这些都是范围广泛的。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。其具体目的是：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 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.