Genetic Analysis of Ethanol Sensitivity in Mice

描述（由申请人提供）：我们实验室的长期目标是 了解乙醇对神经毒性作用的分子机制， 大脑发育。孕妇饮酒可能导致 宫内胎儿神经毒性，即胎儿酒精综合征（FAS）， 受影响儿童的后遗症包括多动症，学习障碍， 智力迟钝抑郁症和精神病既往药理学 有证据表明，N-甲基-D-天冬氨酸（NMDA）受体抑制是 乙醇的重要直接作用，并增加对镇静剂的敏感性 乙醇的作用发生在cAMP第二信使途径的突变中， 果蝇我们将利用基因缺陷的老鼠， 钙刺激腺苷酸环化酶I型（AC 1）和VIII型（AC 8），重要 N-甲基-D-天冬氨酸（NMDA）受体信号传导的介质，以确定 哺乳动物AC功能的改变调节体内乙醇敏感性。的 本提案的具体目标将检验以下假设：AC 1和/或AC 8 缺乏导致1）对细胞凋亡作用的敏感性增加， 乙醇在大脑发育的突触发生期;增加 对乙醇作用的NMDA受体拮抗剂组分的敏感性;和3） 对于类似程度的乙醇介导的 围产期的神经元死亡。这些基因的结果， 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的亚型特异性调制提供基础 作为胎儿酒精综合征的治疗靶点。

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.