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 在癫痫样活动后在特定神经元中受到调节 大鼠全身缺血。 神经元中 GluR2 的选择性丢失会 有利于通过 AMPA 受体增强钙进入这些细胞， 可能会加剧或引发局部兴奋性毒性，因为重组 AMPA 缺乏 GluR2 亚基的受体表现出高钙渗透性。 为了 这就是我们有兴趣具体探索神经元如何 调节这个关键亚基的表达。 这个主要焦点 提案是确定 FluR2 启动子的关键调控元件 控制神经元中 GluR2 的表达。 我们已经亚克隆并 对大鼠 GluR2 基因的 5' 侧翼区域进行了测序，并得到 确定了神经元中控制 GluR2 表达的多个区域。 基于 根据我们的初步数据，我们提出 GluR2 启动子包含 两者都是促进表达的正神经元特异性增强子区域 在神经元中，以及抑制神经元特异性沉默区域 非神经元细胞中的 GluR2 表达。 我们假设变化 识别这些的转录因子的表达 监管位点可能会导致 GluR2 水平发生变化，从而加剧或 引发兴奋性毒性。 这些实验的长期目标是 制定基于预防损失的中风治疗新策略 GluR2 亚基。