Neuronal vs. glial glutamate transport regulation in ALS

ALS 中的神经元与神经胶质细胞谷氨酸转运调节

• 批准号: 7539189
• 负责人: Jeffrey D Rothstein
• 金额: $ 43.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539189
• 关键词: Accounting; Acute; Alternative Splicing; Amyotrophic Lateral Sclerosis; Antibodies; Astrocytes; Biochemical; Biology; Cell Death; Cells; Chronic; Data; Disease; Disease model; Down-Regulation; Financial compensation; Foundations; Functional disorder; Gene Activation; Glutamate Transporter; Glutamates; Homologous Gene; Human; In Vitro; Injury; Laboratories; Lead; Lesion; Literature; Maintenance; Mediating; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Parents; Pattern; Physiological; Physiology; Property; Prosencephalon; Proteins; RNA Splicing; Reaction; Regulation; Relative (related person); Reporter; Reporter Genes; Repression; Rodent; Role; Series; Stress; Synapses; Testing; Tissues; Transgenic Organisms; Variant; base; central nervous system injury; extracellular; human disease; in vivo; injured; nerve injury; nervous system disorder; novel; promoter; protein expression; relating to nervous system; response

DESCRIPTION (provided by applicant): Glutamate transport is critical for the maintenance of low extracellular glutamate and dysregulation of transporters can lead to acute and chronic neurodegeneration. The astroglial transporter EAAT2/GLT1 is the dominant glutamate transporter, accounting for up to 95% of all CNS glutamate transport. Loss of EAAT2 occurs in human diseases and disease models such as ALS, and can contribute to neuronal and astroglial dysfunction and cell death. Recently an alternative splice variant of EAAT2/GLT1, known as EAAT2b/GLT1b, was identified, and early studies suggest it may be present in neurons. Our preliminary data suggest EAAT2b/GLT1b protein expression is regulated and enhanced by neural injury and neurological disease, leading a unique high-level expression in neurons- rather than glia. In this proposal- we will more fully explore the basic biology of this potentially important transport splice variant and its relationship to neuronal/astroglial injury. We hypothesize that EAAT2b/GLT1 is functionally expressed in neural injury as a protective reaction or compensation for the dysregulation of astroglial glutamate transport and may be synaptically active. To test this hypothesis we will: 1) Investigate the altered regional and cellular expression of EAAT2b/GLT1b in ALS and ALS models; 2) Study the function and expression of EAAT2b/GLTb under conditions of neuronal/glial stress; and 3) Analyze the function of GLT1b in neurons vs. astroglia, thru targeted deletion of GLT1/GLT1b from neurons. These studies will help determine if the altered expression of GLT1b in disease is an important physiological response. They will also provide basic physiological properties of the neuronal versus glial pools of GLT1 and GLT1b.

描述（由申请人提供）：谷氨酸转运对于维持低细胞外谷氨酸水平至关重要，转运蛋白的失调可导致急性和慢性神经变性。星形胶质细胞转运蛋白 EAAT2/GLT1 是主要的谷氨酸转运蛋白，占所有中枢神经系统谷氨酸转运的 95%。 EAAT2 的缺失发生在人类疾病和 ALS 等疾病模型中，并可能导致神经元和星形胶质细胞功能障碍以及细胞死亡。最近，EAAT2/GLT1 的另一种剪接变体（称为 EAAT2b/GLT1b）被发现，早期研究表明它可能存在于神经元中。我们的初步数据表明 EAAT2b/GLT1b 蛋白表达受到神经损伤和神经系统疾病的调节和增强，导致神经元而不是神经胶质细胞中独特的高水平表达。在本提案中，我们将更全面地探讨这种潜在重要的转运剪接变体的基础生物学及其与神经元/星形胶质细胞损伤的关系。我们假设 EAAT2b/GLT1 在神经损伤中功能性表达，作为星形胶质细胞谷氨酸转运失调的保护反应或补偿，并且可能具有突触活性。 为了检验这个假设，我们将：1）研究改变的区域和细胞 EAAT2b/GLT1b在ALS和ALS模型中的表达； 2）研究函数和表达 神经元/神经胶质应激条件下的 EAAT2b/GLTb； 3) 通过从神经元中定向删除 GLT1/GLT1b，分析 GLT1b 在神经元与星形胶质细胞中的功能。这些研究将有助于确定疾病中 GLT1b 表达的改变是否是一种重要的生理反应。它们还将提供 GLT1 和 GLT1b 的神经元与神经胶质池的基本生理特性。