Project 3 - Molecular mechanisms of acute ethanol behaviors in C. elegans

项目 3 - 线虫急性乙醇行为的分子机制

• 批准号: 10633319
• 负责人: JILL C BETTINGER
• 金额: $ 18.4万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633319
• 关键词: Acids; Acute; Adolescent; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; American; Animals; Behavior; Behavioral; Biochemistry; Biological; Biological Process; Brain; Caenorhabditis elegans; Candidate Disease Gene; Characteristics; Collaborations; Complex; Defect; Development; Dietary intake; Eicosapentaenoic Acid; Environment; Environmental Risk Factor; Ethanol; Exposure to; FGF21 gene; Fibroblast Growth Factor; Fish Oils; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Human; Investigation; Learning; Lipids; Liver; Mammals; Measures; Mediating; Messenger RNA; Modeling; Molecular; Mus; Nature; Nervous System; Neurons; Omega-3 Fatty Acids; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Proteins; Research Personnel; Risk; Risk Factors; Rodent; Role; Signal Transduction; Source; Supplementation; Testing; Time; Work; adolescent alcohol exposure; alcohol behavior; alcohol effect; alcohol response; alcohol use disorder; behavior test; behavioral phenotyping; behavioral response; candidate identification; design; dietary; disorder risk; fibroblast growth factor 21; gene network; genetic testing; insight; lipid mediator; lipid metabolism; lipidomics; model organism; neural; novel; preference; prenatal; psychologic; response; risk prediction; sedative; translational study

Project Summary – Project 3 The development of alcohol use disorder (AUD) results from an interaction between both environmental and genetic factors. Studies of the impact of environment on the risk to develop AUD have, to date, focused mainly on psychological characteristics (externalizing phenotypes, etc.) or on developmental defects associated with prenatal or adolescent exposure to alcohol. Here, we will study the role of the dietary omega-3 fatty acid eicosapentaenoic acid (EPA), an environmental factor, in adults for a role in modulating the acute behavioral response to ethanol. Our study of the alcohol-naive acute level of response (LR) is significant because this measure is strongly correlated with the liability to develop AUD. Using two model organisms (C. elegans and mouse), we have previously found that dietary omega-3 fatty acid levels significantly impact the acute LR to alcohol in ethanol-naive animals. In worms, we have found specifically that EPA is essential for the development of acute functional tolerance (AFT) to ethanol. We will use two complementary approaches to identify the mechanisms underlying the effects of EPA on the acute behavioral response to ethanol. In Aim 1 we will identify genes whose expression is regulated in response to different EPA levels (depleted, normal levels, above normal levels) in adult C. elegans. We will correlate gene expression changes and the time course of the effect of dietary EPA on AFT. We will directly test the roles of prioritized candidate genes in the development of AFT to identify the molecular pathways that are important for ethanol response behaviors and are affected by EPA levels. In Aim 2, we will use cutting edge lipidomics to determine what lipid species are derived from the dietary EPA. We will correlate the accumulation of EPA derived lipids to the time course of the effects of dietary EPA on AFT. We will identify candidate lipid mediators of the development of AFT. This will implicate molecular pathways in the machinery underlying AFT. These studies will provide novel insight into the roles of lipids in regulating the level of response to alcohol. Determination of the nature of these roles will enable future identification of the protein targets of ethanol, and the regulatory mechanisms affecting those proteins, that are impacted by these lipid-dependent functions. Finally, in Aim 3, we will continue a successful approach that uses the high-throughput genetic power of C. elegans to test the hypothesized roles of genes that have been implicated by other components of the VCU-ARC in behavioral responses to ethanol.

项目摘要-项目3 酒精使用障碍(AUD)的发展是环境和环境之间相互作用的结果 遗传因素。到目前为止，关于环境对发展为ADD的风险的影响的研究主要集中在 论心理特征(外化表型等)或与以下相关的发育缺陷 产前或青春期接触酒精。在这里，我们将研究饮食中omega-3脂肪酸的作用 二十碳五烯酸(EPA)是一种环境因素，在成人中对急性行为的调节作用 对乙醇的反应。我们对酒精幼稚的急性反应水平(LR)的研究意义重大，因为这 衡量标准与发生AUD的风险密切相关。使用两种模式生物(线虫和线虫) 小鼠)，我们先前已经发现，饮食中omega-3脂肪酸水平显著影响急性LR到 酒精类幼稚动物体内的酒精。在蠕虫中，我们特别发现EPA对 急性功能耐受性(AFT)的形成。我们将使用两种互补的方法来 确定EPA对乙醇急性行为反应的潜在作用机制。在目标1中 我们将确定其表达受不同EPA水平(耗尽、正常)调控的基因 水平，高于正常水平)在成年线虫。我们将把基因表达的变化与时间联系起来 膳食EPA对AFT影响的过程。我们将直接测试优先候选基因在 AFT的发展，以确定对酒精反应行为和 受EPA水平的影响。在目标2中，我们将使用尖端脂质组学来确定脂类的种类 源自饮食中的环保局。我们将把EPA衍生的类脂的积累与 日粮EPA对AFT的影响我们将确定AFT发生发展的候选脂质介体。这将是 在AFT背后的机制中涉及分子途径。这些研究将提供新的洞察力 脂类在调节酒精反应水平中的作用。确定这些角色的性质将 使未来能够识别乙醇的蛋白质靶标以及影响这些靶标的调控机制 受这些脂质依赖功能影响的蛋白质。最后，在目标3中，我们将继续成功地 一种利用线虫的高通量遗传力来测试基因假想作用的方法 被VCU-ARC的其他成分牵连到对乙醇的行为反应。