MOLECULAR MECHANISMS OF PROENKEPHALIN GENE REGULATION

点击翻译按钮获取中文摘要

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.