GLUTAMATE RECEPTOR PROCESSING IN AGING

在与年龄相关的改变中涉及的许多受体类型中 正常的神经传递是快速兴奋性谷氨酸激活的 阳离子通道受体(Glur)。因为这些受体被认为是 在建立和维持最佳认知方面发挥核心作用 功能，这些受体的异常表达或调节 与神经元损伤有牵连，了解 调节它们的表达是决定这些受体如何 参与大脑中与年龄相关的变化。单向Glur函数可以 通过亚基的选择性剪接和RNA编辑进行调控 文字记录。这赋予了显著不同的功能特性 在成熟的受体上。在这份为期一年的R03提案中，我将研究 来自不同脑区的GluR亚单位RNA编辑和/或剪接 小鼠、成年小鼠和老年小鼠来检验以下假设。 特定目的1.谷氨酸受体亚基的选择性剪接 大脑老化。要检验的假设是：交替的相对 GluR1、GluR2、GluR3、GluR4剪接转录本在老年人中的改变 相对于幼鼠或成年鼠的小鼠脑。 特定目的2.非NMDA谷氨酸受体亚基的RNA编辑 大脑老化。要检验的假设是：编辑后的相对比率 与未编辑的GluR2、GluR5或GluR6相比，老年小鼠脑中的GluR2、GluR5或GluR6发生了变化 相对于幼鼠或成年鼠。

Among the many receptor types implicated in age-related alterations of normal neurotransmission are the fast excitatory glutamate-activated cationic channel receptors (GLuR). Since these receptors are thought to play a central role in establishing and maintaining optimal cognitive function, and the aberrant expression or regulation of these receptors has been implicated in neuronal damage, understanding the mechanisms that regulate their expression is central to determining how these receptors may participate in age-related changes in the brain. One way GluR function can be regulated is through alternative splicing and RNA editing of subunit transcript. This imparts significantly differently functional properties upon the mature receptor. In this one-year R03 proposal, I will examine GluR subunit RNA editing and/or splicing from various brain regions of young, adult and aged mice to test the following hypothesis. Specific Aim 1. Alternative Splicing of Glutamate Receptor Subunits in the Aging Brain. The hypothesis to be tested is: The relative of alternatively spliced transcripts of GluR1, GluR2, GluR3, GluR4 is altered in the aged mouse brain relative to young or adult mice. Specific Aim 2. RNA editing of Non-NMDA Glutamate Receptor Subunits in the Aging Brain. The hypothesis to be tested is: The relative ratio of edited versus non-edited GluR2, GluR5, or GluR6 is altered in the aged mouse brain relative to young or adult mice.