ETHANOL WITHDRAWAL QTLS AND CANDIDATE GENES

乙醇戒断 QTLS 和候选基因

• 批准号: 2748460
• 负责人: KARI J BUCK
• 金额: $ 10.08万
• 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/2748460
• 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）GABA能降低 传输被认为在发展中发挥着重要作用 酒精依赖/戒断，但负责的特定基因 GABA 能传递的适应性变化仍有待阐明。 在我们的 迄今为止的研究，QTL 分析使用来自 C57BL/6J 和 DBA/2J 近交小鼠品系已鉴定出几个基因座 导致急性酒精戒断严重程度的遗传差异。 一 酒精戒断基因座 (Alcw1) 已定位于高水平 显着性（p<.000015，相对于与 距编码 alpha1、alpha 6 的着丝粒约 10cM GABAA 受体的γ2 和β2 亚基。 另一个基因座 (Alcw2) 有 初步定位在 2 号染色体上，并且在所有三个群体中均显示 与距着丝粒 37 cM 的标记物的关联最强 (p<.002)。 Alcw2 位于编码谷氨酸神经元亚型的两个基因附近 酸性脱羧酶 (GAD)，GABA 合成的限速酶， 距离着丝粒43厘米和9厘米。 本提案的目标 1 和 2 将使用DBA/2J、C57BL/6J和BXD重组近交小鼠来测试 遗传决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 亲本 DBA/2J 和 C57BL/6J 等位基因之间，RNA 转录 蛋白质产品的差异和/或不同的功能特性 已识别的编码 GABAA 受体亚基和/或 GAD 的候选基因 亚型。