Alcohol-responsive protein networks underlying excessive ethanol consumption

过量乙醇消耗背后的酒精反应蛋白网络

基本信息

批准号：
7493330
负责人：
R. DAYNE MAYFIELD
金额：
$ 15.45万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7493330
关键词：
Alcohol consumption Alcoholism Alcohols Animal Model Animals Behavioral Binding Proteins Biochemical Boutos Brain C57BL/6 Mouse California Cell physiology Chimeric Proteins Chromosome Pairing Collaborations Colorado Complementary DNA Complex Cultured Cells Data Dependence Disease Drosophila genus Dynamin Elements Ethanol Event Freezing Funding Gene Cluster Gene Delivery Gene Expression Genes Genome Genomics Genotype Green Fluorescent Proteins Health Sciences Heavy Drinking Human Image Indiana Informatics Inhalation Drug Administration Kinesin Laboratories Maps Microscopy Modeling Molecular Molecular Probes Motor Mus Mutant Strains Mice Neurons Neurotransmitters Nucleus Accumbens Numbers Oregon Organism Palmitoylated Membrane Protein 2 Pattern Phenotype Protein Family Proteins Proteomics Protocols documentation RNA RNA Interference Research Institute Research Personnel Rodent Role Scaffolding Protein Scientist Self Administration Signal Transduction Site Slice Synapses Synapsins Synaptic Transmission System Testing Texas Tissues Transcript Transport Vesicles Universities Withdrawal Work alcohol response animal breeding austin base brain tissue cDNA Arrays design drinking intracellular protein transport member novel programs protein expression protein protein interaction protein transport research study response synaptic function synaptotagmin syntaxin tool trafficking

项目摘要

Genomic and proteomic approaches offer distinct advantages in the search for novel ethanol sites of action because they allow large numbers of elements (RNA transcripts and/or proteins) to be examined simultaneously in an unbiased fashion. INIA West laboratories have performed numerous gene expression studies utilizing both Affymetrix and cDNA microarraysto identify genes that differ in animals bred for high and low ethanol drinking, as well as, those that change in response ethanol administration using drosophila, rodent, and human models of alcoholism. In a significant collaborative effort, INIA West investigators recently worked to consolidate these different microarray experiments and prioritize genes and functionally related groups of genes that were changed significantly in response to ethanol administration. The results of these studies indicate that ethanol alters the expression pattern of a number of genes known to be involved in synapse-related protein trafficking and synaptic transmission. Proteins encoded by the genes are important for a variety of synaptic events including neurotransmitter vesicle transport and targeting (synapsin, syntaxin, dynamin, and synaptotagmin), motor proteins involved in trafficking and targeting of synaptic proteins (kinesin family proteins (KIFs)), and scaffolding proteins (homer and discs-large homolog 2). Interaction proteomics will be used to identify novel protein complexes associated with each of these target proteins in C57BL/6 mice. The effect of excessive ethanol consumption (dependence model of withdrawal-induced drinking (WID)) on these protein complexes will be determined. The overall hypothesis is that excessive ethanol consumption alters protein complexes important for normal trafficking and targeting of proteins involved in synaptic transmission. The resulting changes in trafficking, targeting, and synaptic function underlie ethanol-related phenotypes.

基因组和蛋白质组学方法在寻找新型乙醇作用部位时具有明显的优势因为它们允许检查大量元素（RNA转录本和/或蛋白质）以公正的方式同时。 Inia West Laboratories进行了许多基因表达利用Affymetrix和cDNA微阵列的研究确定了在繁殖高的动物中不同的基因和低乙醇饮用以及使用果蝇对乙醇施用反应的乙醇饮用，啮齿动物和酗酒的人类模型。在一项巨大的合作努力中，Inia West调查人员致力于巩固这些不同的微阵列实验并确定基因和功能相关的优先级响应乙醇给药的基因组发生了重大变化。这些结果研究表明，乙醇改变了许多已知参与的基因的表达模式与突触相关的蛋白质运输和突触传播。由基因编码的蛋白质很重要对于包括神经递质囊泡传输和靶向的各种突触事件（突触素，语法素，， Dynamin和Synaptotagmin），参与运输和靶向突触蛋白的运动蛋白（运动蛋白家族蛋白（KIFS））和脚手架蛋白（Homer和Discs-large同源物2）。相互作用蛋白质组学将用于鉴定与这些靶蛋白相关的新型蛋白质复合物 C57BL/6鼠。过度乙醇消耗的效果（提取诱导的依赖模型将确定这些蛋白质复合物上的饮用（WID）。总体假设是过多乙醇消耗改变蛋白质复合物对于正常运输和靶向蛋白质很重要参与突触传播。贩运，靶向和突触功能的结果变化基础与乙醇相关的表型。