TRANSCRIPTION FACTORS MEDIATING OPIOID PLASTICITY

这项提案的长期目标是更好地理解神经系统如何 活动调节阿片样物质基因的表达，并了解这是如何 这一过程有助于环境和药物引起的变化， 神经系统 更好地了解这些过程将有助于 定义成瘾，依赖， 和吸毒行为。 本研究的主要目的 我们的建议没有改变，但已经修改了我们的研究， 在过去的几年里取得了进展。 主要重点是描述 细胞内信号通路与几种不同的 介导活性依赖性调节的转录因子复合体 脑啡肽原基因的表达 特征为第二信使诱导型DNA增强子。 研究将集中 AP-1、ATF和CREB核蛋白复合物的定义成分 参与脑啡肽原转录的调节。 功能和 与脑啡肽原诱导的DNA增强子的生化相互作用， 通过细胞内信号传导途径传递的信号将被 研究了 最近的研究结果表明，生长和神经营养 因子通过一种新的ras依赖性激活脑啡肽原的转录 信号通路，导致CREB在Ser-133磷酸化。 基于 在这些发现的基础上，我们进一步强调了 为了进一步了解这一途径的作用， 这条通路在神经信号传导和前脑啡肽基因调控中的作用。

The long range goals of this proposal are to better understand how neural activity regulates opioid gene expression, and to understand how this process contributes to environmental- and drug-induced changes in the nervous system. A better understanding of these processes will help to define the adaptive biochemical changes underlying addiction, dependence, and drug-seeking behaviors. The primary objectives of this research proposal have not changed but have been modified as our research has progressed over the pst few years. The major focus is to characterize the interaction of intracellular signaling pathways with several different transcription factors complexes that mediate activity-dependent regulation of proenkephalin gene expression via their interaction with a well characterized second messenger inducible DNA enhancer. Studies will focus on defining components of the AP-1, ATF, and CREB nucleoprotein complexes involved in the regulation of proenkephalin transcription. Functional and biochemical interactions with the proenkephalin inducible DNA enhancer and signals transmitted through intracellular signaling pathways will be investigated. Recent findings indicate that growth and neurotrophic factors activate proenkephalin transcription via a novel ras-dependent signaling pathway that results in CREB phosphorylation at Ser-133. Based upon these discoveries we have increased our emphasis on further characterization of this pathway in order to further understand the role of this pathway in neural signaling and proenkephalin gene regulation.