GENES RELATED TO DRUG ABUSE--REGULATION OF OPIOID PEPTIDE GENES

与药物滥用相关的基因--阿片肽基因的调控

• 批准号: 3853715
• 负责人: G R UHL
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3853715
• 关键词: drug abuse; drug addiction; drug tolerance; enkephalins; fertility; gene expression; genetic promoter element; genetically modified animals; human subject; laboratory mouse; neurons; neuropeptides; pain threshold; pharmacogenetics; spinal nerves; spinal trigeminal nucleus; transcription factor

Drugs alter the expression of many important genes in the brain. These changes in gene expression are likely to contribute to long-term drug effects, such as tolerance and dependence. Continuing studies of the genes encoding endogenous morphine-like peptides suggest that drug-induced gene regulation depends on the circuits connecting to the neuron and the duration of drug exposure. During the past year, the laboratory has monitored cellular levels of neuropeptide mRNAs and of the transcription factor genes that may alter expression of these mRNAs to assess gene regulation related to functional activity in these neurons. In studies completed during this year, transsynaptic regulation of preproenkephalin expression in pain-modulating neurons of the nucleus caudalis of the spinal tract of the trigeminal was described in detail. and the AP-1 and CREB family transcription factors that could participate in this regulation were identified. Transgenic mice possessing a specific portion of the preproenkephalin promoter were produced, and their responsiveness to only certain trans-synaptic activators of preproenkephalin expression noted. Interesting effects of expressed minigene constructs on male fertility and testicular function were found. Finally, approaches to directly modifying these transcription factor pathways in brain with intraparenchymal injection of modified oligonucleotides were validated. These approaches allow understanding of mechanisms important for attempts to therapeutically manipulate drug influences on gene expression. Preliminary results from a human study using opiate antagonists to change the expression of these opioid peptide genes provide evidence for the efficacy of such targeted therapies.

药物会改变大脑中许多重要基因的表达。 这些 基因表达的变化可能有助于长期药物治疗 影响，例如耐受性和依赖性。继续研究 编码内源吗啡样肽的基因表明 药物诱导的基因调控取决于连接至 神经元和药物暴露的持续时间。 在过去的一年里，实验室监测了细胞水平 神经肽 mRNA 和可能改变的转录因子基因 这些 mRNA 的表达可评估与功能相关的基因调控 这些神经元的活动。 在今年完成的研究中， 前脑啡肽原表达的跨突触调节 脊髓尾核的疼痛调节神经元 对三叉神经进行了详细的描述。以及 AP-1 和 CREB ​​系列 可以参与这种调节的转录因子是 确定。 转基因小鼠拥有特定的部分 产生了前脑啡肽原启动子，并且它们仅对 注意到前脑啡肽原表达的某些跨突触激活剂。 表达的小基因构建体对男性生育力的有趣影响 并发现睾丸功能。最后，直接接近 修改大脑中的这些转录因子通路 验证了修饰寡核苷酸的实质内注射。 这些方法可以帮助理解对于尝试很重要的机制 治疗上操纵药物对基因表达的影响。 使用阿片拮抗剂改变人体研究的初步结果 这些阿片肽基因的表达为 此类靶向治疗的疗效。