MECHANISMS OF RAT GLUR2 GENE EXPRESSION IN NEURONS

越来越多的文献表明，GluR 2 mRNA水平下降- 在癫痫样活动后的特定神经元中调节， 大鼠全脑缺血。 神经元中GluR 2的选择性丢失将 有利于增强钙通过AMPA受体进入这些细胞， 可能加剧或引发局部兴奋性毒性，因为重组AMPA 缺乏GluR 2亚基的受体表现出高钙渗透性。 为 这就是为什么我们对探索神经元 调节这个关键亚基的表达。 这个主要的焦点 一项建议是确定FluR 2启动子的关键调控元件 控制神经元中GluR 2的表达。 我们已经亚克隆， 对大鼠GluR 2基因的5 '侧翼区进行测序， 鉴定了神经元中控制GluR 2表达的多个区域。 基于 根据我们的初步数据，我们提出GluR 2启动子含有 既有一个阳性的神经元特异性增强子区域， 在神经元中，以及一个神经元特异性沉默区， GluR 2在非神经元细胞中的表达。 我们假设， 识别这些转录因子的转录因子表达 调节位点可能导致GluR 2水平的变化， 引发兴奋性毒性。 这些实验的长期目标是 开发一种新的中风治疗策略， GluR 2亚基的

A growing body of literature shows that GluR2 mRNA levels are down- regulated in specific neurons following epileptiform-like activity and global ischemia in rats. The selective loss of GluR2 in neurons would favor enhanced calcium entry via AMPA receptors into these cells and could exacerbate or initiate local excitotoxicity, since recombinant AMPA receptors lacking a GluR2 subunit exhibit high calcium permeability. For this reason we are interested in exploring specifically how neurons regulate expression of this key subunit. this primary focus of this proposal is to identify the critical regulatory elements FluR2 promoter that control GluR2 expression in neurons. We have subcloned and sequenced the 5'-flanking region of the rat GluR2 gene and have identified multiple regions governing GluR2 expression in neurons. Based on our preliminary data, we proposed that the GluR2 promoter contains both a positive, neuron-specific enhancer region that promotes expression in neurons, as well as a neuron specific silencer region that represses GluR2 expression in non-neuronal cells. We hypothesize that changes in the expression of the transcription factors that recognize these regulatory sites may lead to changes in GluR2 levels that exacerbate or initiate excitotoxicity. The long-term goal of these experiments is to develop a new strategy for stroke therapy based on preventing the loss of the GluR2 subunit.