SYNGAP REGULATION OF NMDA RECEPTOR-MEDIATED NEURONAL CELL DEATH

SYNGAP 调节 NMDA 受体介导的神经细胞死亡

• 批准号: 7720359
• 负责人: PASQUALE MANZERRA
• 金额: $ 2.06万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720359
• 关键词: Automobile Driving; Cell Death; Cessation of life; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Development; Experimental Models; Funding; Grant; Hand; In Vitro; Institution; Ischemia; Mediating; Nerve Degeneration; Physiological; Play; Property; Proteins; Protocols documentation; RNA Interference; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Stroke; Synapses; Synaptic plasticity; Tertiary Protein Structure; Therapeutic Agents; Traumatic Brain Injury; United States National Institutes of Health; excitotoxicity; neuron loss; neuronal survival; protein expression; receptor

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. Physiological activation of MNDA receptors (NMDARs) plays a critical role in synaptic plasticity and neuronal survival. Exessive activation of NMDARs on the other hand has been implicated in mediating neurodegeneration following ischemia and traumatic brain injury (TBI). Although many studies have shown promising neuroprotective properties for NMDAR antagonists in experimental models of Stroke and TBI, clinical trials using such antagonists have failed. The issue at hand is to separate the positive benefits of NMDAR activation from the negative ones. The hypothesis driving the proposed research is that SynGAP (synaptic Ras GRPase activating protein) serves as a regulatory switch controlling NMDAR-mediated activation of both pro-survival and pro-death signaling. The specific aims, which include 1) Determining the functional protein domain(s), which mediate SynGAP's role in NMDAR-mediated excitotoxicity and 2) establishing a protocol to selectively knockdown SynGAP expression in vitro using RNAi, are created to provide an assessment of SynGAP's role in regulating NMDAR-mediated cell death in vitro and identify a strategy for the development of potential therapeutic agents.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 MNDA受体（NMDARs）的生理激活在突触可塑性和神经元存活中起关键作用。另一方面，NMDAR的过度激活涉及介导缺血和创伤性脑损伤（TBI）后的神经变性。尽管许多研究已经显示NMDAR拮抗剂在中风和TBI的实验模型中具有有希望的神经保护特性，但是使用这种拮抗剂的临床试验失败了。目前的问题是将NMDAR激活的积极益处与消极益处分开。推动这项研究的假设是SynGAP（突触Ras GRP 3激活蛋白）作为一个调节开关，控制NMDAR介导的促生存和促死亡信号的激活。具体目的包括1）确定介导SynGAP在NMDAR介导的兴奋性毒性中的作用的功能性蛋白质结构域和2）建立使用RNAi在体外选择性敲低SynGAP表达的方案，创建这些目的以提供对SynGAP在体外调节NMDAR介导的细胞死亡中的作用的评估并鉴定用于开发潜在治疗剂的策略。