Translational regulation of glutamate transporter EAAT2 & therapeutic application

谷氨酸介导的兴奋性毒性被认为与许多神经疾病的发病机制有关。在疾病条件下，当突触前终末释放增加或突触间隙重摄取不足时，细胞外谷氨酸浓度可能会升高。过量的谷氨酸会导致谷氨酸受体的过度刺激，导致神经元损伤或死亡。防止兴奋性毒性的一种方法是阻断谷氨酸受体；然而，这种方法在人类身上并不是很成功。另一种方法是增强谷氨酸的再摄取。胶质细胞谷氨酸转运体EAA T2是终止突触传递的主要谷氨酸转运体。保护兴奋性毒性神经元损伤的一个潜在的治疗方法是激活EAA T2蛋白的表达，并促进谷氨酸的重新摄取。通过高通量筛选，我们最近发现了两类能够特异性激活EAA T2蛋白表达的化合物。第一个目标是优化这些化合物，以提高它们的安全性和有效性。本项目的第二个目标是评估目标1产生的所有类似物在培养的原代星形胶质细胞和野生型小鼠中的生物活性。第三个目的是确定化合物诱导EAAT2表达的信号通路。重要的是，该提案融合了研究谷氨酸转运体分子生物学/生物化学的实验室的经验和能力，以及致力于开发神经退行性疾病新疗法的中心的专业知识。我们的最终目标是开发一种治疗效果显著的新药，通过诱导EAA T2的表达。

Glutamate-mediated excitotoxicity is believed to be involved in the pathogenesis of many neurological disorders. Under disease conditions, elevated extracellular glutamate concentrations can occur when the release from presynaptic terminals is augmented or when the reuptake from the synaptic cleft is insufficient. Excessive glutamate can cause over-stimulation of glutamate receptors and result in neuronal injury or death .. One way to prevent excitotoxicity is to block glutamate receptor; however, this approach is not very successful in human .. Another approach is enhanced glutamate reuptake .. The glial glutamate transporter EAA T2 is the major glutamate transporter in terminating synaptic transmission. One potential therapeutic approach to protect against excitotoxic neuron damage is to activate EAA T2 protein expression and boost glutamate reuptake .. By high-throughput screening, we have recently identified two classes of compounds which can specifically activate EAA T2 protein expression. The first objective is to optimize these compounds to increase their safety and efficacy The second aim of this project is to evaluate the biological activity of all analogues emerging from Aim 1 in cultured primary astrocytes as well as in wild-type mice .. The third aim is to identify signaling pathways involved in compound-induced EAAT2 expression .. Importantly, the proposal merges the experience and capabilities of the laboratories investigating the molecular biology/biochemistry of glutamate transporters with the expertise of a Center devoted to the development of novel therapies for neurodegenerative diseases. Our ultimate goal is to develop a new drug with remarkable therapeutic effect by inducing EAA T2 expression.