Therapeutic Expression of Glial Glutamate Transporters

神经胶质谷氨酸转运蛋白的治疗性表达

• 批准号: 7475723
• 负责人: Jeffrey D Rothstein
• 金额: $ 35.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475723
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; Brain Neoplasms; Carrier Proteins; Cells; Chronic; Data; Disease; Disease Progression; Disease model; Drug usage; Epilepsy; Excitatory Amino Acid Transporter 2; Fluorescence; GLAST Protein; Gene Activation; Gene Expression; Genomics; Glutamate Transporter; Glutamates; In Vitro; Injury; Lactams; Length; Link; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neurologic; Neurons; Neuroprotective Agents; Pattern; Pharmaceutical Preparations; Prosencephalon; Reagent; Regulation; Reporter; Rodent; Seizures; Spinal Cord; Standards of Weights and Measures; Synapses; Testing; Therapeutic; Transgenic Mice; Transgenic Model; base; in vivo; motor neuron degeneration; nerve injury; nervous system disorder; novel; prevent; promoter; protein expression; tumor growth

DESCRIPTION (provided by applicant): The astroglial transporter GLT-1/EAAT2 is responsible for the largest percentage of glutamate transport in forebrain. Abnormal expression/function of EAAT2 is common to sporadic ALS, to transgenic models of the disease, as well as other neurological injuries. The mechanism that underlies transporter deregulation is not fully understood, but may involve altered promoter activation. We hypothesize that regulating expression of these proteins could provide powerful therapies to retard disease progression. Initial studies provide exciting evidence that increasing EAAT2 protein/activity can retard neurodegeneration in ALS animal models; diminish seizures associated with epilepsy, and retard brain tumor growth. In this proposal we will use recently generated GLT1 and GLAST-promoter reporter mice to evaluate the regulation of transporters. These rodents will be used to study the dysregulation of transporters in neurodegenerative disease. We propose to alter transporter gene activation as a novel means to delay neurodegenerative disease. The completion of these studies will provide a comprehensive understanding of transporter regulation in normal and abnormal CNS and their potential as neuroprotectants. Specifically we propose: 1) To understand the normal regional and temporal regulation of astroglial glutamate transporter gene expression, thru analysis of GLAST-BAC and GLT1-BAC promoter reporter expressing transgenic mice; 2) To test the hypothesis that altered glutamate transporter expression in neurological injury is the result of promoter deregulation; 3) To determine if altered cellular expression of astroglial glutamate transporters can prevent neuronal degeneration. Using drugs capable of increasing GLT1 and GLAST promoter expression we will determine if increased expression of the astroglial transporter(s) can prevent neural injury in vivo and we will determine if cell specific expression of glutamate transport alters chronic neurodegeneration using an animal model of amyotrophic lateral sclerosis. We hypothesize that over expression of GLT1 or GLAST will be neuroprotective in disease models. Over all Significance: In this proposal, we will develop a basic understanding of expression of GLAST and GLT I, discover reagents that can alter glutamate transporter activity, and determine if these approaches are useful for chronic neurological insults.

描述（由申请方提供）：星形胶质细胞转运蛋白GLT-1/EAAT 2负责前脑中最大百分比的谷氨酸转运。EAAT 2的异常表达/功能在散发性ALS、该疾病的转基因模型以及其他神经损伤中很常见。转运蛋白失调的机制还不完全清楚，但可能涉及启动子激活的改变。我们假设，调节这些蛋白质的表达可以提供有效的治疗方法来延缓疾病的进展。最初的研究提供了令人兴奋的证据，即增加EAAT 2蛋白/活性可以延缓ALS动物模型中的神经变性;减少与癫痫相关的癫痫发作，并延缓脑肿瘤生长。在这个提议中，我们将使用最近产生的GLT 1和GLAST启动子报告小鼠来评估转运蛋白的调节。这些啮齿动物将用于研究神经退行性疾病中转运蛋白的失调。我们建议改变转运蛋白基因的激活作为一种新的手段来延缓神经退行性疾病。这些研究的完成将提供对正常和异常CNS中转运蛋白调节及其作为神经保护剂的潜力的全面了解。具体而言，我们建议：1）通过分析GLAST-BAC和GLT1-BAC启动子报告基因表达转基因小鼠，了解星形胶质细胞谷氨酸转运蛋白基因表达的正常区域和时间调节; 2）验证神经损伤中谷氨酸转运蛋白表达改变是启动子失调的结果的假设; 3）确定星形胶质细胞谷氨酸转运蛋白的细胞表达改变是否可以预防神经元变性。使用能够增加GLT 1和GLAST启动子表达的药物，我们将确定星形胶质细胞转运蛋白的表达增加是否可以预防体内神经损伤，并且我们将使用肌萎缩侧索硬化症的动物模型确定谷氨酸转运的细胞特异性表达是否改变慢性神经变性。我们假设GLT 1或GLAST的过度表达将在疾病模型中具有神经保护作用。总体意义：在这项提案中，我们将开发一个基本的理解GLAST和GLT I的表达，发现试剂，可以改变谷氨酸转运蛋白的活性，并确定这些方法是否是有用的慢性神经损伤。