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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

基本信息

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
项目类别：
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

项目摘要

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