TRANSCRIPTION FACTORS MEDIATING OPIOID PLASTICITY

这项提议的长期目标是更好地理解 神经活动如何调节阿片基因的表达，以及 了解这些流程如何对环境和环境做出贡献 药物引起神经系统的稳定/适应性变化。一个 更好地理解这些过程将有助于定义 成瘾、戒断、 和吸毒行为。这项工作的主要目标是 研究建议没有改变。主要关注点仍然是 鉴定和鉴定介导转录的转录因子 脑啡肽原基因表达的活性依赖性调控 通过它们与特征良好的第二信使的互动 可诱导的DNA增强子。研究将集中在定义 AP-L/AP-4和核因子-L/ZFX核蛋白复合体的组成 它调节脑啡肽原转录的调节。 与前脑啡肽的功能和生化相互作用 可诱导的DNA增强子和信号通过 将对细胞内信号通路进行研究。近期 研究结果表明，Jund激活了脑啡肽原的转录 以一种完全依赖于循环AMP的方式 依赖蛋白激酶(PKA)，一种可以 被JunB有效屏蔽。我们已经加强了对 根据上述内容理解Jund/JunB的监管 研究结果，以及最近发现滥用药物，如 可卡因、安非他明和吗啡调节AP-1(FOS/Jun 复合体)在脑中的表达。总而言之，这项分析将 在分子水平上定义细胞内相互作用 信号通路、转录因子和DNA元件 它们调节内源性阿片信号以响应 神经递质、药物和突触输入。

The long range goals of this proposal are to better understand how neural activity regulates opioid gene expression, and to understand how these processes contribute to environmental and drug induced stable/adaptive changes in the nervous system. A better understanding of these processes will help to define the adaptive biochemical changes underlying addiction, withdrawal, and drugseeking behaviors. The primary objectives of this research proposal have not changed. The major focus is still to identify and characterize transcription factors which 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 the AP-l/ AP-4, and NF-l/ ZFX nucleoprotein complexes which mediate 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 JunD activates proenkephalin transcription in a fashion which is completely dependent upon the cyclic-AMP dependent protein kinase (PKA), an effect which can be effectively blocked by JunB. We have increased our emphasis on understanding regulation by JunD/JunB in light of the above findings, and the recent discovery that drugs of abuse such as cocaine, amphetamine, and morphine regulate AP-1 (fos/jun complexes) expression in brain. Together, this analysis will define at the molecular level interactions between intracellular signaling pathways, transcription factors, and the DNA elements which regulate endogenous opioid signaling in response to neurotransmitters, drugs, and synaptic inputs.