MT COBRE: MOLEC MODULATION OF GLUTAMATE TRANSPORTER EXPRESSION: AIDS DEMENTIA
MT COBRE:谷氨酸转运蛋白表达的分子调节:艾滋病痴呆
基本信息
- 批准号:7381173
- 负责人:
- 金额:$ 17.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-05-01 至 2007-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prolonged increases in the extracellular concentration of glutamate result in the over stimulation of glutamate receptors and leads to the excitotoxic death of neurons. Excitotoxicity has been associated with a number of chronic, and acute neurodegenerative diseases including, Amyotrophic lateral sclerosis (ALS), epilepsy, Parkinson's disease, Huntingtons' disease, AIDS dementia, glaucoma, ischemia and brain trauma. A system of Na-dependent, high affinity, excitatory amino acid (EAA) transporters plays a critical role in regulating the extracellular concentrations of glutamate within the CNS and thus maintains the balance between physiological and pathological conditions. The rapid clearance of glutamate by these transporters facilitates signal termination, transmitter recycling, and the maintenance of glutamate below excitotoxic levels. A variety of substrate and nonsubstrate inhibitors of the glutamate transporters have been used to study the functional roles of these important proteins. Unfortunately, none of the glutamate transporter inhibitors characterized to date have the ability to act in a cell type specific manner and only a limited number of these inhibitors exhibit transporter isotype specificity. This lack of transporter and cell type specificity has led to conflicting opinions regarding the roles of specific transporter isotypes in neuroprotection and neurodegeneration associated with excitotoxic disease. In order to address this deficiency, we propose to use AAV1 vectors to establish cell type-specific overexpression and knock down of recombinant EAAT2 and EAAT3 in murine hippocampal slice cultures. Using this in vitro model, we will examine the impact of modified transporter expression on the cellular localization of these transporters as well as other critical glutamate receptors. Furthermore, we will examine the effect of overexpressing recombinant transporters on functional uptake activity in neurons and astrocytes. Most importantly, we will investigate the contribution of specific transporter isotypes to neuroprotection and neurodegeneration following an excitotoxic insult.
本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者(PI)可能已经从另一个NIH来源获得了主要资金,因此可以在其他CRISP条目中表示。列出的机构是中心的,不一定是研究者的机构。细胞外谷氨酸浓度的持续升高导致谷氨酸受体的过度刺激,并导致神经元的兴奋性毒性死亡。兴奋性毒性与许多慢性和急性神经退行性疾病有关,包括肌萎缩性侧索硬化症(ALS)、癫痫、帕金森病、亨廷顿氏病、艾滋病、痴呆、青光眼、缺血和脑外伤。na依赖性、高亲和性、兴奋性氨基酸(EAA)转运体系统在调节中枢神经系统内谷氨酸的细胞外浓度中起关键作用,从而维持生理和病理条件之间的平衡。这些转运体对谷氨酸的快速清除促进了信号终止、递质循环和谷氨酸维持在兴奋毒性水平以下。谷氨酸转运体的各种底物和非底物抑制剂已被用于研究这些重要蛋白质的功能作用。不幸的是,迄今为止表征的谷氨酸转运蛋白抑制剂都没有能力以细胞类型特异性的方式起作用,只有有限数量的这些抑制剂表现出转运蛋白同型特异性。这种转运蛋白和细胞类型特异性的缺乏导致了关于特定转运蛋白同型在神经保护和与兴奋性毒性疾病相关的神经变性中的作用的相互矛盾的观点。为了解决这一缺陷,我们提出利用AAV1载体在小鼠海马切片培养中建立细胞类型特异性的重组EAAT2和EAAT3的过表达和敲低。利用这种体外模型,我们将研究转运蛋白表达对这些转运蛋白以及其他关键谷氨酸受体的细胞定位的影响。此外,我们将研究过表达重组转运蛋白对神经元和星形胶质细胞功能性摄取活性的影响。最重要的是,我们将研究特定转运蛋白同型在兴奋性毒性损伤后的神经保护和神经变性中的作用。
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID J POULSEN', 18)}}的其他基金
Global, Cell Type Specific Modulation of Selected Glutamate Transporters
选定谷氨酸转运蛋白的全局、细胞类型特异性调节
- 批准号:
7240394 - 财政年份:2007
- 资助金额:
$ 17.55万 - 项目类别:
Global, Cell Type Specific Modulation of Selected Glutamate Transporters
选定谷氨酸转运蛋白的全局、细胞类型特异性调节
- 批准号:
7345415 - 财政年份:2007
- 资助金额:
$ 17.55万 - 项目类别:
Support cell specific expression of regulatable Math-1
支持可调节 Math-1 的细胞特异性表达
- 批准号:
7140495 - 财政年份:2005
- 资助金额:
$ 17.55万 - 项目类别:
Support cell specific expression of regulatable Math-1
支持可调节 Math-1 的细胞特异性表达
- 批准号:
6969991 - 财政年份:2005
- 资助金额:
$ 17.55万 - 项目类别:
MODULATION STRATEGIES TO ENHANCE GLUTAMATE TRANSPORT
增强谷氨酸转运的调节策略
- 批准号:
7011773 - 财政年份:2004
- 资助金额:
$ 17.55万 - 项目类别:
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