ETHANOL WITHDRAWAL QTLS AND CANDIDATE GENES

乙醇戒断 QTLS 和候选基因

• 批准号: 2894142
• 负责人: KARI J BUCK
• 金额: $ 10.39万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2894142
• 关键词: GABA receptor; brain electrical activity; disease /disorder proneness /risk; drug withdrawal; ethanol; genetic mapping; genetic polymorphism; genetic strain; genetic transcription; glutamate decarboxylase; laboratory mouse; neurogenetics; nucleic acid sequence; protein structure function

DESCRIPTION: (Adapted from APPLICANT'S ABSTRACT) Decreased GABAergic transmission is thought to play an important role in the development of alcohol dependence/withdrawal, but the specific genes responsible for adaptive changes in GABAergic transmission remain to be elucidated. In our studies to date, QTL analysis using three populations derived from the C57BL/6J and DBA/2J inbred mouse strains have identified several loci that contribute to genetic differences in acute alcohol withdrawal severity. One alcohol withdrawal locus (Alcw1) has been localized at a high level of significance (p<.000015, relative to the null hypothesis of no linkage to an approximate 10cM from the centromere that encodes the alpha1, alpha 6, gamma2 and beta 2 subunits of GABAA receptors. Another locus (Alcw2) has tentatively been mapped on chromosome 2, and in all three populations showed the strongest association with markers located 37 cM from the centromere (p<.002). Alcw2 maps near two genes encoding neuronal subtypes of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, located 43cM and 9 cM from the centromere. Aims 1 and 2 of this proposal will use DBA/2J, C57BL/6J, and BXD recombinant inbred mice to test the hypothesis that genetically determined differences in acute alcohol withdrawal severity are correlated with differences in cDNA coding sequence between parental DBA/2J and C57BL/6J alleles, RNA transcriptional differences and/or different functional properties for the protein products of identified candidate genes encoding GABAA recptor subunits and/or GAD subtypes.

描述：（改编自申请人的摘要）降低了Gabaergic 人们认为传播在发展中起着重要作用 酒精依赖/提取，但负责的特定基因 GABA能传播的自适应变化尚待阐明。 在我们的 迄今为止的研究，QTL分析使用来自 C57BL/6J和DBA/2J Inbred小鼠菌株已经确定了几个基因座 导致急性酒精戒断严重程度的遗传差异。 一 酒精提取基因座（ALCW1）已定位在高水平 显着性（p <.000015，相对于无链接的无键假设 距编码alpha1，alpha 6的丝粒大约10厘米 GAMMA2和Beta 2个GABAA受体的亚基。 另一个基因座（alcw2） 暂时映射在2号染色体上，在所有三个种群中均显示 与距Centromere 37厘米的标记的最强关联 （p <.002）。 谷氨酸的神经元亚型的两个基因附近的alcw2地图 酸脱羧酶（GAD），GABA合成中的速率限制酶， 位于距Centromere的43厘米和9厘米处。 该提议的目标1和2 将使用DBA/2J，C57BL/6J和BXD重组近交小鼠进行测试 遗传确定急性酒精差异的假设 戒断严重程度与cDNA编码序列的差异相关 在父母DBA/2J和C57BL/6J等位基因之间，RNA转录 蛋白质产物的差异和/或不同的功能特性 编码GABAA接收亚基和/或GAD的已识别候选基因 亚型。