The transcriptional co-factor LMO4 and ethanol drinking

转录辅助因子 LMO4 和乙醇饮用

基本信息

批准号：
9179842
负责人：
ROBERT O. MESSING
金额：
$ 18.55万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179842
关键词：
Address Adult Alcohol consumption Amygdaloid structure Animals Automobile Driving Binding Bioinformatics Brain Brain region Cocaine Corpus striatum structure Data Data Analyses Development Dorsal Estrogen Receptor alpha Estrogens Ethanol Ethanol dependence Female Fostering Funding Future Gene Expression Gene Expression Profiling Genes Goals Grant Heavy Drinking Human Light Medial Molecular Mus Mutation Nucleus Accumbens Phenotype Play Population Prefrontal Cortex Procedures Public Health RNA Interference Recruitment Activity Rewards Rodent Role Staging Subfamily lentivirinae Sucrose Testing Transcriptional Regulation Ventral Tegmental Area Wild Type Mouse Work addiction drinking genetic manipulation high reward high risk interest male neuroadaptation prevent problem drinker research study response sex small hairpin RNA transcription factor

项目摘要

PROJECT SUMMARY Neuroadaptive changes in gene expression due to repeated ethanol consumption is a major mechanism that underlies the transition from moderate to excessive drinking. Gene expression profiling studies of human alcoholics and ethanol dependent rodents have identified a multitude of ethanol-responsive gene networks. Little is known about how these networks are recruited into a neuroadaptive response. One mechanism could involve ethanol regulation of transcriptional co-regulators that bind and modulate the activity of several transcription factors, thereby orchestrating a diverse neuroadaptive transcriptional network. However, very few studies have identified transcriptional co-regulators in the brain that respond to ethanol and in turn regulate ethanol consumption. In ongoing experiments we found evidence that the transcriptional co-regulator Lim-only 4 (LMO4) regulates ethanol consumption. LMO4 is expressed in brain regions important for addiction and recent work indicates that it plays an important role in cocaine sensitization and conditioned reward for sucrose. Our initial results show that LMO4 levels in the nucleus accumbens decrease during intermittent, binge-like ethanol consumption, and a gene trap mutation in the Lmo4 gene, which reduces LMO4 levels by 50%, increases the development of excessive ethanol consumption in male C57BL/6J mice. Given these findings we propose that LMO4 is an ethanol-responsive, neuroadaptive transcriptional co-regulator that regulates ethanol consumption. This hypothesis will be addressed in two Specific Aims: (1) to determine whether LMO4 regulates ethanol consumption in both sexes, and (2) to identify brain regions in which LMO4 acts to moderate ethanol consumption. Should the results show that LMO4 in specific regions of the adult brain regulates ethanol consumption in male and female mice, future studies aimed at determining how ethanol regulates LMO4 and how LMO4 regulates ethanol consumption could shed new light on a fundamental mechanism by which ethanol provokes a neuroadaptive response that leads to excessive drinking.

项目概要由于反复消耗乙醇而导致的基因表达的神经适应性变化是一个主要因素从适度饮酒到过度饮酒的转变的机制。基因表达对人类酗酒者和依赖乙醇的啮齿动物的分析研究已经发现了许多乙醇反应基因网络。人们对这些网络是如何招募的知之甚少进入神经适应性反应。一种机制可能涉及乙醇调节结合并调节多种转录因子活性的转录共调节因子，从而编排多样化的神经适应性转录网络。然而，极少数研究已经发现大脑中对乙醇和酒精有反应的转录共调节因子进而规范乙醇消费。在正在进行的实验中，我们发现证据表明转录共调节因子 Lim-only 4 (LMO4) 调节乙醇消耗。 LMO4 在重要的大脑区域表达成瘾和最近的研究表明它在可卡因致敏和蔗糖的条件奖励。我们的初步结果表明细胞核中的 LMO4 水平间歇性、暴饮暴食期间伏隔核减少，这是一个基因陷阱 Lmo4 基因突变使 LMO4 水平降低 50%，从而促进雄性 C57BL/6J 小鼠过量乙醇消耗。鉴于这些发现，我们提出 LMO4 是一种乙醇反应性、神经适应性的调节乙醇消耗的转录共调节因子。这个假设将是解决两个具体目标：(1) 确定 LMO4 是否调节乙醇消耗 (2) 确定 LMO4 调节乙醇的大脑区域消耗。如果结果表明 LMO4 在成人大脑的特定区域调节雄性和雌性小鼠的乙醇消耗量，未来的研究旨在确定乙醇如何消耗调节 LMO4 以及 LMO4 如何调节乙醇消耗可能为揭示乙醇激发神经适应性反应的基本机制酗酒。