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: 8379587
• 负责人: MICHAEL F MILES
• 金额: $ 13.44万
• 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/8379587
• 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 Expression Profile; Gene Targeting; Gene Transfer; Genes; Genetic; Genetic Variation; Harvest; Hour; Human; Inbred Strains Mice; Inbreeding; Laboratories; Light; Link; Maps; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Motor Activity; Mus; Nucleus Accumbens; Other Genetics; Pathway Analysis; Pathway interactions; 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.

对人类和动物模型的研究表明，对乙醇的急性行为反应具有预测作用 关于长期乙醇饮用行为风险的价值。在啮齿动物模型中，运动激活和 抗焦虑样活性是两种被广泛记录的对乙醇的急性行为反应。压力、焦虑 乙醇或乙醇戒断对焦虑的影响已被认为是焦虑的重要因素。 酗酒和累犯的起源。我们实验室的最新结果已经确定了显着的定量 使用焦虑的明暗盒转换模型研究急性乙醇抗焦虑样活性的性状位点（QTL） 跨越 33 个 BXD 重组近交小鼠品系。同时，我们生成了微阵列数据集 来自相同的盐水或急性乙醇处理的 BXD 系，用于前额皮质和伏隔核。 最近的研究表明，结合基因表达和行为的 QTL 分析可以改善 行为 QTL 候选基因的鉴定。这种“表达遗传学”有能力识别 高度相关的基因表达模式网络。将基因表达网络与 行为 QTL 可以为此类表达网络的功能相关性提供证据 复杂特征背后的候选机制。该开发项目还将进一步使用电力 VCU-ARC 的总体实验设计优先考虑与急性相关的基因表达网络 小鼠的乙醇行为反应。我们将： 1）完成腹侧被盖区的微阵列研究 跨 33 个 BXD R1 系 +/- 乙醇（1.8 g/kg x 4 小时）； 2) 识别与相关的基因表达网络 乙醇对运动活动和焦虑样行为的急性影响的行为测量； 3) 通过 潜在的跨物种比较（项目 2、3 和试点 1）和生物信息学优先顺序（核心 2） PCR验证的表达变化，我们将选择有限数量的候选者进行直接验证研究 在小鼠中。后者将使用现有无效突变小鼠系或接受过治疗的动物的行为测试 病毒载体基因传递。我们期望这能为与相关的基因网络提供一种新的验证。 对乙醇的急性行为反应。此外，我们的小鼠基因靶向和行为测定将 为该中心的项目2,3和试点1的研究提供资源。我们共同期待新的协同效应 这些关于对急性乙醇反应的基因网络的跨物种研究。