ROLE OF SYNGAP IN REGULATING NMDA RECEPTOR-MEDIATED NEURONAL EXCITOTOXICITY

点击翻译按钮获取中文摘要

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. 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.