SYNGAP REGULATION OF NMDA RECEPTOR-MEDIATED NEURONAL CELL DEATH

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 MNDA受体(NMDAR)的生理激活对突触可塑性和神经元存活起着至关重要的作用。另一方面，NMDAR的过度激活与脑缺血和创伤性脑损伤(TBI)后的神经退行性变有关。尽管许多研究表明NMDAR拮抗剂在中风和脑外伤的实验模型中具有良好的神经保护作用，但使用此类拮抗剂的临床试验都失败了。眼下的问题是将NMDAR激活的积极好处与消极好处区分开来。支持这项研究的假设是SynGAP(突触Ras GRPase激活蛋白)作为一个调节开关，控制NMDAR介导的有利于生存和有利于死亡的信号的激活。具体目标包括：1)确定介导SynGAP在NMDAR介导的兴奋性毒性中作用的功能蛋白结构域(S)；2)建立一种使用RNAi选择性抑制SynGAP体外表达的方法，以评估SynGAP在体外调节NMDAR介导的细胞死亡中的作用，并确定潜在治疗药物的开发策略。

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.