Project 1: Cross Species Characterization of Gene Networks in Acute Responses

项目 1：急性反应中基因网络的跨物种表征

• 批准号: 7674954
• 负责人: MICHAEL F MILES
• 金额: $ 10.33万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7674954
• 关键词: ARHGEF5 gene; Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Behavior; Behavioral; Behavioral Assay; Bioinformatics; Boxing; Candidate Disease Gene; Complex; Data; Data Set; Development; Dopamine; Ethanol; Experimental Designs; Gene Delivery; Gene Expression; Gene Targeting; Gene Transfer; Genes; Genetic; Genetic Variation; Harvest; Hour; Human; Inbred Strains Mice; Laboratories; Link; Maps; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Motor Activity; Mus; Nucleus Accumbens; Other Genetics; Pathway Analysis; Pathway interactions; Pattern; Pilot Projects; Predictive Value; Prefrontal Cortex; Quantitative Trait Loci; Recombinants; Resources; Risk; Rodent Model; Saline; Scheme; Stress; TNFRSF5 gene; Validation; Ventral Tegmental Area; Viral; Viral Vector; Western Blotting; Work; alcohol behavior; alcohol effect; alcohol response; alcoholism therapy; behavior measurement; behavior test; design; drinking; drinking behavior; embryonic stem cell; follow-up; gene discovery; improved; interest; novel; null mutation; progenitor; recidivism; research study; response; tool; trait

Studies in both humans and animal models show that acute behavioral responses to ethanol have predictive value regarding risk for long term ethanol drinking behavior. In rodent models, locomotor activation and anxiolytic-like activity are two widely documented acute behavioral responses to ethanol. Stress, anxiety and effects of ethanol or ethanol-withdrawal on anxiety have been proposed as important factors in the genesis of alcoholism and recidivism. Recent results in our laboratory have identified significant quantitative trait loci (QTLs) for acute ethanol anxiolytic-like activity using the light-dark box transition model of anxiety across 33 BXD recombinant inbred mouse strains. Simultaneously, we have generated microarray datasets from the same saline or acute ethanol-treated BXD lines, for prefrontal cortex and nucleus accumbens. Recent studies suggest that combining QTL analysis of gene expression and behavioral can improve identification of candidate genes for behavioral QTLs. Such "expression genetics" has the power to identify networks of highly correlated gene expression patterns. Correlating genetic expression networks with behavioral QTLs could provide evidence for the functional relevance of such expression networks and candidate mechanisms underlying complex traits. This developmental project will furthermore use the power of the overall experimental design of the VCU-ARC to prioritize gene expression networks linked to acute ethanol behavioral responses in mice. We will: 1) Complete microarray studies for ventral tegmental area across 33 BXD Rl lines +/- ethanol (1.8 g/kg x 4 hours); 2) Identify gene expression networks correlated with behavioral measures of acute ethanol effects on locomotor activity and anxiety-like behavior; and 3) Through potential cross-species comparison (Projects 2, 3 and Pilot 1) and bioinformatics prioritization (Core 2) of PCR-verified expression changes, we will select a limited number of candidates for direct verification studies in mice. The latter will use behavioral testing of existing null mutation mouse lines or animals treated with viral-vector gene delivery. We expect this to provide a novel validation of gene networks correlated with the acute behavioral responses to ethanol. Furthermore, our mouse gene targeting and behavioral assays will provide resources for studies in Projects 2,3 and Pilot 1 of this Center. Together we expect a novel synergy of these cross-species studies on gene networks responding to acute ethanol.

在人类和动物模型中的研究表明，对酒精的急性行为反应具有预测性 长期饮酒行为的风险价值。在啮齿动物模型中，运动激活和 抗焦虑活性是乙醇引起的两种常见的急性行为反应。压力、焦虑 而酒精或戒酒对焦虑的影响被认为是影响焦虑的重要因素。 酗酒与累犯的成因。我们实验室的最新结果已经确定了显著的 利用焦虑的明暗盒转换模型检测急性乙醇类焦虑活性的特征基因(QTL 在33个BXD重组近交系小鼠品系中。同时，我们已经生成了微阵列数据集 来自相同的生理盐水或急性乙醇处理的BXD系，用于前额叶皮质和伏隔核。 最近的研究表明，结合对基因表达和行为的QTL分析可以改善 行为QTL候选基因的筛选。这样的“表达遗传学”有能力识别 高度相关的基因表达模式网络。基因表达网络与 行为QTL可以为这种表达网络的功能相关性提供证据，并 复杂性状背后的候选机制。这个开发项目将进一步利用这一力量 VCU-ARC的总体实验设计，以确定与急性白血病相关的基因表达网络的优先顺序 小鼠的酒精行为反应。我们将：1)完成腹侧被盖区的微阵列研究 33个BXD RL品系+/-乙醇(1.8g/kg×4小时)；2)鉴定与 急性酒精对运动活动和焦虑样行为的影响的行为测量；以及3)通过 潜在的跨物种比较(项目2、3和试点1)和生物信息学优先次序(核心2) 经PCR验证的表达变化，我们将选择有限数量的候选进行直接验证研究 在老鼠身上。后者将对现有的零突变小鼠品系或经 病毒载体基因传递。我们希望这将为与基因网络相关的基因网络提供一个新的验证 对酒精的急性行为反应。此外，我们的小鼠基因定位和行为分析将 为该中心项目2、3和试点1的研究提供资源。我们期待着一种新的协同效应 这些关于急性乙醇反应的基因网络的跨物种研究。