MOLECULAR MECHANISMS OF PROENKEPHALIN GENE REGULATION

我的长期目标是了解神经活动是如何 调节基因表达，并最终了解这些过程是如何 有助于环境和药物引起的稳定/适应性变化 神经系统。更好地理解这些过程将有助于我们 了解毒品成瘾背后的适应性生理变化， 容忍、戒毒和寻毒行为。 学习、记忆、长期影响的分子机制 成瘾药物，以及神经系统的其他稳定/适应性变化 在很大程度上是未知的。随着神经元转导的发现 环境输入对基因表达的变化，该假说 研究发现，对基因表达的跨突触调节可能诱导 许多形式的神经信号可塑性背后的生化变化。 要理解这些过程，有必要确定这两条途径 和调节学习效果的机制、精神药物和 其他突触介导的基因表达过程。神经 对阿片前体前脑啡肽的调节是一个很好的模型 研究基因突触调节机制的系统 表达是因为：i)转录既被激活又被抑制 突触信号，ii)大脑中的事件，如电刺激 它们诱导的LTP也会引起戏剧性和长期的变化 脑啡肽原基因表达，iii)基因产物脑啡肽， 调节不同神经通路的重要信号分子包括 止痛、奖励和激励状态，以及荷尔蒙释放。这个 本研究提案的主要目标是确定和表征 调节脑啡肽原基因表达的核蛋白复合体 确定这些核蛋白复合体如何介导突触调节 前脑啡肽原通过它们与一种具有良好特性的相互作用转录 第二信使诱导的DNA增强子。在本协议所涵盖的期间内 提议，研究将侧重于确定ENKTF-1和FOS/JUN的组成部分 介导前脑啡肽突触调节的核蛋白复合体 抄写。此外，它们的功能和生化相互作用 通过前脑啡肽诱导的DNA增强子和信号传递 将通过细胞内信号通路进行研究。因为 上述转录因子被两种基因激活 神经递质和药理物质它们可以被认为是 毒品行动的重要目标。在理解这些方面的进展 机制应提供对致病机制和治疗的洞察力 许多影响神经系统的疾病。

My long range goals are to develop an understanding of how neural activity regulates gene expression, and to ultimately understand how these processes contribute to environmental and drug induced stable/adaptive changes in the nervous system. A better understanding of theses processes will help us understand the adaptive physiologic changes underlying drug addiction, tolerance, withdrawal, and drug-seeking behaviors. The molecular mechanisms underlying learning, memory, long-term effects of addictive drugs, and other stable/adaptive changes in the nervous system are largely unknown. With the discovery that neurons transduce environmental inputs into changes in gene expression, the hypothesis has emerged that trans-synaptic regulation of gene expression may induce the biochemical changes underlying many forms of neural signaling plasticity. To understand these processes it is necessary to identify both the pathways and mechanisms mediating the effects of learning, psychotropic drugs, and other synaptically mediated processes on gene expression. Neural regulation of the opioid precursor, proenkephalin, is an excellent model system to study mechanisms underlying synaptic regulation of gene expression because: i) transcription is both activated and repressed by synaptic signals, ii) in the brain, events such as electrical stimulation which induce LTP also induce dramatic and long lasting changes in proenkephalin gene expression, iii) the gene products, enkephalins, are important signaling molecules regulating diverse neural pathways including analgesia, reward and motivational states, and hormone release. The primary objective of this research proposal is to identify and characterize nucleoprotein complexes which regulate proenkephalin gene expression and to determine how these nucleoprotein complexes mediate synaptic regulation of proenkephalin transcription via their interaction with a well characterized second messenger inducible DNA enhancer. In the period covered by this proposal, studies will focus on defining components of ENKTF-1 and Fos/Jun nucleoprotein complexes which mediate synaptic regulation of proenkephalin transcription. In addition their functional and biochemical interactions with the proenkephalin inducible DNA enhancer and signals transmitted through intracellular signaling pathways will be investigated. Because the transcription factors described above are activated by both neurotransmitters and pharmacologic agents they can be considered to be important targets of drug action. Progress in understanding these mechanisms should provide insight into the pathogenesis and treatment of many disorders affecting the nervous system.