Epistatic Modifiers and Novel Genetic Contributions to Binge-like Drinking and Motivational Effects of Alcohol

项目摘要 酒精使用障碍（AUD）与个人和社会的重大成本有关。遗传 和环境因素有助于AUDs和过量饮酒的风险， 特定的风险基因将允许新的预防和治疗策略。Glycoprotein 1（GLO1）是一种 酒精研究中的新目标，以前在我们实验室的啮齿动物研究中确定。Glo1过表达 增加了小鼠的狂饮，表明与过量酒精摄入有关。内生 GLO1的底物甲基乙二醛（MG）作为GABAA受体的部分激动剂。药理学和 已经显示了增加MG水平的遗传操作（即GLO 1抑制、GLO 1基因敲低 减少小鼠的狂饮，提供了GLO1调节酒精的可能机制。 消费这个研究项目的目标是确定Glo1和其他潜在的相关基因的作用。 遗传风险因素过量饮酒的小鼠模型的暴饮暴食。目标1将使用一本小说 产生在不同遗传学上过表达Glo1的近交系小鼠的F1组的育种策略 背景将对这些小鼠进行酗酒样饮酒的表型分析。两部分基因组 关联研究将用于：1）映射Glo1的上位性修饰物，其增强或抑制Glo1的作用， 饮酒，和2）确定潜在的数量性状基因座与狂饮。目标2将 研究为什么Glo1改变酒精摄入量，通过测试Glo1表达的变化改变酒精摄入量的假设， 对酒精或酒精厌恶的奖励增强效应的敏感性。总之，这些实验将给 我们更好地了解Glo1过度表达如何导致过度饮酒的风险， 突出显示了改变这种风险的其他基因。这种双重方法可以确定新的目标和战略， 预防或治疗饮酒中毒

Project Summary Alcohol use disorders (AUDs) are associated with significant costs to both the individual and society. Genetic and environmental factors contribute to the risk of AUDs and excessive drinking, and a better understanding of the specific risk genes will allow for novel strategies for prevention and treatment. Glyoxalase 1 (GLO1) is a new target in alcohol research identified previously by rodent studies in our lab. Overexpression of Glo1 increases binge-like drinking in mice, suggesting involvement in excessive alcohol intake. The endogenous substrate of GLO1, methylglyoxal (MG), acts as a partial agonist at GABAA receptors. Pharmacological and genetic manipulations that increase MG levels (i.e. GLO1 inhibition, Glo1 gene knockdown) have been shown to reduce binge-like drinking in mice, providing a possible mechanism through which GLO1 modifies alcohol consumption. The goal of this fellowship project is to determine the role of Glo1 and other potential related genetic risk factors for excessive drinking in a mouse model of binge-like intake. Aim 1 will use a novel breeding strategy to generate an F1 panel of inbred mice overexpressing Glo1 on different genetic backgrounds. These mice will be phenotyped for alcohol binge-like drinking. A two-part genome wide association study will be used to 1) map epistatic modifiers of Glo1 that enhance or suppress its effects on alcohol drinking, and 2) identify potential quantitative trait loci associated with binge-like drinking. Aim 2 will investigate why Glo1 modifies alcohol intake, by testing the hypothesis that changes in Glo1 expression alter sensitivity to the reward-enhancing effects of alcohol or alcohol aversion. Together, these experiments will give us a better understanding of how Glo1 overexpression contributes to risk of excessive drinking, and will highlight other genes that modify this risk. This dual approach may identify novel targets and strategies for preventing or treating drinking to intoxication