TRANSCRIPTION FACTORS MEDIATING OPIOID PLASTICITY

这项提议的长期目标是更好地理解神经性 活性调节阿片基因的表达，并理解这是如何 过程有助于环境和药物诱导的变化 神经系统。更好地理解这些过程将有助于 定义成瘾、依赖、 和毒品寻觅行为。这项研究的主要目标是 建议没有改变，但已经像我们的研究那样被修改了 在太平洋标准时间的几年里取得了进展。主要的焦点是描述 几种不同的细胞内信号转导途径的相互作用 介导活性依赖调控的转录因子复合体 通过与井的相互作用来表达前脑啡肽基因 表征了第二信使诱导的DNA增强子。研究将集中于 关于AP-1、ATF和CREB核蛋白复合体的定义成分 参与前脑啡肽转录的调节。功能和 与脑啡肽原诱导的DNA增强子和 通过细胞内信号通路传递的信号将是 调查过了。最近的发现表明，生长和神经营养 因子通过一种新的依赖ras的途径激活脑啡肽原转录 导致CREB在Ser-133处磷酸化的信号通路。基座 在这些发现之后，我们更加重视进一步的 这一途径的特征，以进一步了解其作用 这一途径在神经信号转导和脑啡肽原基因调控中起重要作用。

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.