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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：
8114524
负责人：
CHIEN-LIANG GLENN LIN
金额：
$ 9.58万
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 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114524
关键词：
Acute Adult All-Trans-Retinol Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Animals Astrocytes Biochemistry Biological Ceftriaxone Cerebral Ischemia Cessation of life Corticosterone DNA Microarray Chip Development Disease Epilepsy Evaluation Excitatory Amino Acid Transporter 2 Future Glutamate Receptor Glutamate Transporter Glutamates Goals Human Huntington Disease In Vitro Intraperitoneal Injections Intrathecal Injections Investigation Laboratories Lead Mediating Messenger RNA Metabolic Microarray Analysis Molecular Molecular Biology Molecular Probes Neurodegenerative Disorders Neuronal Injury Neurons Oxazoles Pathogenesis Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Play Presynaptic Terminals Property Regulation Regulatory Element Role Safety Screening Result Series Signal Pathway Solubility Spinal Cord Stroke Structure-Activity Relationship Synapses Synaptic Cleft Synaptic Transmission Testing Therapeutic Therapeutic Effect Toxic effect Transgenic Mice Translational Regulation Translations Trauma Untranslated Regions Visceral pain Wild Type Mouse analog cytotoxicity excitotoxicity experience extracellular high throughput screening in vivo lead series mouse model nervous system disorder novel prevent protein expression reuptake 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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.

DOI：
10.1084/jem.20140413
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Takahashi K;Kong Q;Lin Y;Stouffer N;Schulte DA;Lai L;Liu Q;Chang LC;Dominguez S;Xing X;Cuny GD;Hodgetts KJ;Glicksman MA;Lin CL
通讯作者：
Lin CL

Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus.