Modeling genetically controlled DBH activity in mice

小鼠基因控制的 DBH 活性建模

• 批准号: 7084672
• 负责人: DAVID WEINSHENKER
• 金额: $ 7.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084672
• 关键词: alleles; behavioral /social science research tag; biological models; catecholamines; cocaine; disulfiram; dopamine beta monooxygenase; drug addiction; electroporation; enzyme activity; gene expression; genetic polymorphism; genetic regulation; genetically modified animals; laboratory mouse; model design /development; neurochemistry; neurotransmitter biosynthesis; polymerase chain reaction; pulsed field gel electrophoresis; southern blotting; substance abuse related behavior

DESCRIPTION (provided by applicant): Dopamine beta-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, adrenergic neurons, and adrenal chromaffin cells. Therefore, DBH controls both NE synthesis and the DA/NE ratio in noradrenergic cells. DBH enzymatic activity in humans varies between individuals. A common polymorphism (a C to T change at position -1021) has been identified in the human Dbh gene that accounts for most of the genetic variability and about half of the total variability observed in DBH enzymatic activity. DBH has recently become of interest in the field of drug addiction for two reasons. First, the rewarding and aversive effects of cocaine appear to be influenced by Dbh genotype in humans. Second, the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence. Because of technical and ethical issues in human research, very little is known about the neurochemical consequences of the Dbh C-1021T polymorphism. Therefore, it is of interest to create a rodent model of the C-1021T polymorphism and assess both neurochemical and behavioral differences between the C and the T alleles of Dbh. We propose to create transgenic mice bearing a bacterial artificial chromosome (BAG) that contains either the C allele or the T allele of the human Dbh gene. Completion of this aim will provide us with the tools necessary to ascertain how the C-1021T polymorphism controls DBH enzymatic activity, its effect on catecholamine neurochemistry, and the behavioral consequences of these changes, especially as they relate to drug addiction.

描述（由申请人提供）：多巴胺β-羟化酶（DBH）将多巴胺（DA）转换为去肾上腺素能神经元，肾上腺素能神经元和肾上腺染色体细胞中的去甲肾上腺素（NE）。因此，DBH控制去甲肾上腺素能细胞中的NE合成和DA/NE比。人类中的DBH酶活性在个体之间有所不同。在人类DBH基因中已经确定了一种常见的多态性（AC到T变化-1021），该基因构成了大多数遗传变异性，约占DBH酶活性中观察到的总变异性的一半。 DBH最近因两个原因而成为吸毒领域的感兴趣。首先，可卡因的有意义和厌恶作用似乎受到人类DBH基因型的影响。其次，DBH抑制剂二硫酸氨基酯作为可卡因依赖性的药物疗法表现出了希望。由于人类研究中的技术和道德问题，对DBH C-1021T多态性的神经化学后果知之甚少。因此，创建C-1021T多态性的啮齿动物模型并评估DBH的C和T等位基因之间的神经化学和行为差异是有意思的。我们建议创建带有细菌人造染色体（BAG）的转基因小鼠，其中包含人类DBH基因的C等位基因或T等位基因。该目标的完成将为我们提供确定C-1021T多态性如何控制DBH酶活性，对Catecholamine神经化学的影响以及这些变化的行为后果的必要工具，尤其是在与药物成瘾有关的情况下。