MECHANISMS OF RAT GLUR2 GENE EXPRESSION IN NEURONS

大鼠 GLUR2 基因在神经元中表达的机制

• 批准号: 2674536
• 负责人: SCOTT James MYERS
• 金额: $ 0.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2674536
• 关键词: AMPA receptors; action potentials; brain electrical activity; calcium flux; gene expression; genetic promoter element; genetic regulatory element; laboratory rat; neurogenetics; tissue /cell culture; transcription factor

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.

越来越多的文献表明glur2 mRNA水平下降 - 在癫痫样活性和 大鼠全球缺血。 神经元中Glur2的选择性丢失将 利用通过AMPA受体进入这些细胞的增强的钙进入，并且 由于重组AMPA，可能会加剧或启动局部兴奋性毒性 缺乏GLUR2亚基的受体表现出较高的钙渗透性。 为了 这个原因我们有兴趣特别探索神经元如何 调节该关键亚基的表达。 这是这个主要重点 建议是确定关键的调节元素FLUR2启动子 控制神经元中的glur2表达。 我们已经取代了 测序了大鼠glur2基因的5'频偏区，并具有 确定了在神经元中glUR2表达的多个区域。 基于 在我们的初步数据上，我们提出Glur2启动子包含 两者都是阳性的，神经元特异的增强子区域，可促进表达 在神经元中以及抑制神经元特异性消音区域 在非神经元细胞中的GLUR2表达。 我们假设变化 识别这些转录因子的表达 监管部位可能导致加剧或 引发兴奋性。 这些实验的长期目标是 制定一种基于防止损失的新策略 Glur2亚基。