Catecholamine Transcriptional Regulation and Response t*

儿茶酚胺转录调节和反应 t*

• 批准号: 6533685
• 负责人: Elaine J. Lewis
• 金额: $ 15.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533685
• 关键词: alcoholic beverage consumption; behavioral /social science research tag; behavioral genetics; cAMP response element binding protein; central nervous system; cooperative study; dopamine beta monooxygenase; ethanol; gene expression; genetic regulatory element; laboratory mouse; laboratory rat; microarray technology; neural transmission; neuropharmacology; neurotransmitter metabolism; norepinephrine; self medication; substance abuse related behavior; toxin metabolism; tyrosine 3 monooxygenase

The neural response of organisms to alcohol consumption involves extensive cell-cell communication, activation of signal transduction pathways and changes in gene transcription. The complexity of the response has hindered reaching basic mechanistic understandings of the critical events. Recently, advances in genetic analysis and technology allow the evaluation of the role of an individual gene in the response to alcohol consumption. Using genetic technology, it was found that mice lacking the ability to synthesize the neurotransmitter norepinephrine (NE) exhibit altered responses to ethanol administration. These mice have reduced preference for ethanol self-administration and are more sensitive to the sedative effects of ethanol, suggesting a role for NE in the response of the nervous system to ethanol. Unrelated studies found that treatment of neuroblastoma cell cultures with ethanol resulted in a specific elevation of mRNAs and proteins corresponding to two enzymes involved in the biosynthesis of NE, dopamine beta-hydroxylase (DBH which catalyzes the production of NE from dopamine, and tyrosine hydroxylase (TH), responsible for the formation of DOPA. The focus of this application is to further understand the cellular response to ethanol by identification and characterization of the components involved in transcriptional regulation of the DBH and TH genes. In addition, this proposal is designed to further explore the involvement of NE in the transcriptional adaptation to ethanol. The specific aims are to: (1) Define the ethanol-responsive genetic regulatory elements of the rat TH and DBH genes, and the factors which bind to those elements. (2) Evaluate the importance of NE neurotransmission to alcohol responsiveness in vivo by comparing gene expression patterns in the amygdala, ventral tegmentum and nucleus accumbans between wild type and DBH deficient mice. (3) Characterize the response of the TH and DBH genes to acute and chronic ethanol administration in the mouse CNS. The results of these experiments will further our understanding of the role NE synthesis and neurotransmission in the cellular adaptation to alcohol treatment.

生物体对饮酒的神经反应涉及广泛的 细胞间通讯、信号转导途径的激活和 基因转录的变化。响应的复杂性阻碍了 对关键事件达成基本的机制理解。最近， 遗传分析和技术的进步可以评估其作用 单个基因对饮酒的反应。利用遗传 技术，发现小鼠缺乏合成 神经递质去甲肾上腺素 (NE) 对乙醇的反应发生改变 行政。这些小鼠对乙醇的偏好降低 自我给药并对乙醇的镇静作用更敏感， 表明 NE 在神经系统对乙醇的反应中发挥作用。 不相关的研究发现，神经母细胞瘤细胞培养物的处理 乙醇导致相应的 mRNA 和蛋白质的特定升高 涉及 NE 生物合成的两种酶：多巴胺β-羟化酶 （DBH 催化多巴胺和酪氨酸产生 NE 羟化酶（TH），负责形成多巴。本次的重点 应用是为了进一步了解细胞对乙醇的反应 所涉及组件的识别和表征 DBH 和 TH 基因的转录调控。此外，本提案 旨在进一步探索NE在转录中的参与 对乙醇的适应。具体目标是： (1) 定义乙醇响应 大鼠 TH 和 DBH 基因的遗传调控元件，以及 与这些元素结合的因素。 (2)评估NE的重要性 通过比较基因对体内酒精反应的神经传递 杏仁核、腹侧被盖和伏核的表达模式 野生型和 DBH 缺陷小鼠之间的比较。 (3) 表征响应 TH 和 DBH 基因对小鼠中枢神经系统急性和慢性乙醇给药的影响。 这些实验的结果将进一步我们对 NE 作用的理解 细胞适应酒精的合成和神经传递 治疗。