Genetic Analysis of Ethanol Sensitivity in Mice

小鼠乙醇敏感性的遗传分析

• 批准号: 6365684
• 负责人: Louis J Muglia
• 金额: $ 24.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365684
• 关键词: GABA receptor; NMDA receptors; adenylate cyclase; alcoholic beverage consumption; apoptosis; biological signal transduction; blood tests; calcium channel; chemosensitizing agent; developmental neurobiology; electrophysiology; enzyme activity; ethanol; gene mutation; gene targeting; genetic manipulation; genetically modified animals; laboratory mouse; molecular genetics; neural degeneration; neural plasticity; neural transmission; neurotoxicology; newborn animals; synaptogenesis; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term goals of our laboratory are to understand the molecular mechanisms for the neurotoxic effects of ethanol on the developing brain. Alcohol consumption by pregnant women can result in intrauterine fetal neurotoxicity, i.e. fetal alcohol syndrome (FAS), with sequelae in affected children including hyperactivity, learning disorders, mental retardation, depression, and psychosis. Previous pharmacological evidence has implicated N-methyl-D-aspartate (NMDA) receptor inhibition as an important direct effect of ethanol, and increased sensitivity to the sedative effect of ethanol occurs with mutations in the cAMP second messenger pathway in drosophila. We will utilize mice genetically deficient in the calcium-stimulated adenylyl cyclases type I (AC1) and VIII (AC8), important mediators of N-methyl-D-aspartate (NMDA) receptor signaling, to determine if alteration in mammalian AC function modulates ethanol sensitivity in vivo. The specific aims of this proposal will test the hypotheses that AC1 and/or AC8 deficiency results in 1) increased sensitivity to the apoptotic actions of ethanol during the synaptogenesis period of brain development; increase in sensitivity to the NMDA receptor antagonist component of ethanol action; and 3) greater long-term behavioral deficits for similar degrees of ethanol-mediated neuronal death in the perinatal period.] The results of these genetic, pharmacological, and molecular biological studies will further elucidate the molecular mechanisms by which ethanol alters neuronal physiology and survival and provide the basis for considering isoform-specific modulation of AC function as a therapeutic target for fetal alcohol syndrome.

描述（由申请人提供）：我们实验室的长期目标是 了解乙醇神经毒性作用的分子机制 正在发育的大脑。孕妇饮酒会导致 宫内胎儿神经毒性，即胎儿酒精综合症（FAS）， 受影响儿童的后遗症包括多动症、学习障碍、 精神发育迟滞、抑郁症和精神病。以前的药理学 有证据表明 N-甲基-D-天冬氨酸 (NMDA) 受体抑制是一种 乙醇的重要直接作用，并增加对镇静剂的敏感性 乙醇的作用随着 cAMP 第二信使途径的突变而发生 果蝇。我们将利用基因缺陷的小鼠 钙刺激腺苷酸环化酶 I 型 (AC1) 和 VIII (AC8)，重要 N-甲基-D-天冬氨酸 (NMDA) 受体信号转导介质，以确定是否 哺乳动物 AC 功能的改变可调节体内乙醇敏感性。这 该提案的具体目标将测试 AC1 和/或 AC8 的假设 缺乏导致 1) 对细胞凋亡作用的敏感性增加 大脑发育突触发生期间的乙醇；增加 对乙醇作用的 NMDA 受体拮抗剂成分的敏感性；和 3) 类似程度的乙醇介导的长期行为缺陷更大 围产期神经元死亡。]这些遗传的结果， 药理学和分子生物学研究将进一步阐明 乙醇改变神经元生理和存活的分子机制 并为考虑 AC 异构体​​特异性调制提供基础 作为胎儿酒精综合症的治疗靶点。