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: 10429953
• 负责人: JILL C BETTINGER
• 金额: $ 18.9万
• 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/10429953
• 关键词: Acute; Adolescent; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; American; Animal Model; 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 structure; 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; design; dietary; disorder risk; gene network; genetic testing; insight; lipid mediator; lipid metabolism; lipidomics; novel; preference; prenatal; psychologic; relating to nervous system; response; 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.

项目概要-项目3 酒精使用障碍（AUD）的发展是由环境和 遗传因素到目前为止，环境对澳元风险的影响研究主要集中在 心理特征（外化表型等）或与以下疾病相关的发育缺陷 产前或青少年接触酒精。在这里，我们将研究饮食中欧米茄-3脂肪酸的作用， 二十碳五烯酸（EPA），一种环境因子，在成人中调节急性行为 乙醇的反应。我们对未饮酒的急性反应水平（LR）的研究是有意义的，因为这 该指标与开发澳元的责任密切相关。利用两种模式生物（C.线虫和 小鼠），我们以前发现饮食中的ω-3脂肪酸水平显著影响急性LR， 酒精在酒精实验动物中的作用在蠕虫中，我们特别发现EPA对于 对乙醇的急性功能性耐受（AFT）的发展。我们将使用两种互补的方法， 确定EPA对乙醇急性行为反应影响的机制。目标1 我们将鉴定其表达响应于不同EPA水平（耗尽的、正常的）而被调节的基因， 水平，高于正常水平）在成人C。优雅的我们将把基因表达的变化和 日粮EPA对AFT的影响过程。我们将直接测试优先候选基因在其中的作用 开发AFT以识别对乙醇响应行为重要的分子途径， 受EPA水平的影响。在目标2中，我们将使用最先进的脂质组学来确定脂质种类 源自膳食EPA。我们将把EPA衍生的脂质的积累与代谢的时间进程相关联。 EPA对AFT的影响。我们将确定候选脂质介质的发展AFT。这将 暗示了AFT机制的分子途径。这些研究将提供新的见解， 脂质在调节酒精反应水平中的作用。确定这些作用的性质将 使未来能够识别乙醇的蛋白质靶点，以及影响这些靶点的调节机制。 蛋白质，受这些脂质依赖性功能的影响。最后，在目标3中，我们将继续成功地 利用C.秀丽线虫来测试基因的假设作用 这与VCU-ARC的其他成分在对乙醇的行为反应中有关。