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Translational regulation of glutamate transporter EAAT2 & therapeutic application

谷氨酸转运蛋白 EAAT2 的翻译调控

基本信息

批准号：
7736933
负责人：
CHIEN-LIANG GLENN LIN
金额：
$ 45.04万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7736933
关键词：
1-Phosphatidylinositol 3-Kinase Acute Adult Alzheimer&apos s Disease Amino Acid Transporter Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Astrocytes Biochemistry Biological Ca(2+)-Calmodulin Dependent Protein Kinase Calcium/calmodulin-dependent protein kinase Cells Cerebral Ischemia Cessation of life Cultured Cells Cyclic AMP-Dependent Protein Kinases Development Disease Epilepsy Evaluation Excitatory Amino Acid Antagonists Excitatory Amino Acids Exposure to Glutamate Receptor Glutamate Transporter Glutamates Glycogen Synthase Kinase 3 Goals Human Huntington Disease In Vitro Intraperitoneal Injections Intrathecal Injections Laboratories Lead Mediating Membrane Messenger RNA Metabolic Mitogen-Activated Protein Kinases Molecular Biology Molecular Probes Mus Neurodegenerative Disorders Neuronal Injury Neurons Neurotransmitters Nuclear Oxazoles Parkinson Disease Pathogenesis Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phosphotransferases Play Presynaptic Terminals Property Protein Kinase C Proteins Role Safety Screening Result Signal Pathway Solubility Stroke Structure-Activity Relationship Synaptic Cleft Synaptic Transmission System Testing Therapeutic Therapeutic Effect Toxic effect Translational Regulation Trauma Visceral pain Wild Type Mouse analog cytotoxicity drug development excitotoxicity experience extracellular high throughput screening in vivo lead series nervous system disorder novel prevent protein expression receptor reuptake therapeutic target treatment effect uptake

项目摘要

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.

谷氨酸介导的兴奋性毒性被认为参与许多神经系统疾病的发病机制。在疾病条件下，当从突触前末梢的释放增加或当从突触间隙的再摄取不足时，可发生升高的细胞外谷氨酸浓度。过量的谷氨酸会引起谷氨酸受体的过度刺激，并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，这种方法在人类中不是很成功。另一种方法是增强谷氨酸再摄取。神经胶质谷氨酸转运体EAA T2是终止突触传递的主要谷氨酸转运体。保护免受兴奋性毒性神经元损伤的一种潜在治疗方法是激活EAA T2蛋白表达并促进谷氨酸再摄取。通过高通量筛选，我们最近鉴定了两类可以特异性激活EAA T2蛋白表达的化合物。第一个目标是优化这些化合物，以提高其安全性和有效性。该项目的第二个目标是评估Aim 1中出现的所有类似物在培养的原代星形胶质细胞以及野生型小鼠中的生物活性。第三个目的是鉴定参与化合物诱导的EAAT 2表达的信号通路。重要的是，该提案将研究谷氨酸转运蛋白分子生物学/生物化学的实验室的经验和能力与致力于开发神经退行性疾病新疗法的中心的专业知识相结合。我们的最终目标是通过诱导EAA T2的表达来开发一种具有显著治疗效果的新药。