Proteomic Dissection of Withdrawal-Induced Excessive Drinking

戒断引起的过度饮酒的蛋白质组学解析

基本信息

批准号：
7672576
负责人：
Christine C Wu
金额：
$ 24.11万
依托单位：
UNIVERSITY OF COLORADO DENVER
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/7672576
关键词：
Alcohol consumption Alcohol withdrawal syndrome Alcoholism Alcohols Amino Acid Substitution Amino Acids Amygdaloid structure Animal Model Animals Behavior Behavioral Biochemistry Brain Breeding Chronic Cluster Analysis Collaborations Colorado Complement Complex Databases Dependence Development Dissection Electron Microscopy Fractionation Future Genes Genetic Genotype Goals Heavy Drinking Individual Differences Isotopes Knowledge Label Letters Longitudinal Studies Mass Spectrum Analysis Membrane Membrane Proteins Methodology Modeling Molecular Morphology Mus Neurosciences Phenotype Post-Translational Protein Processing Procedures Proteins Proteomics Relapse Relative (related person)Research Personnel Rewards Sampling Shotguns Structure Subcellular Fractions Technology Time Tissues Transgenic Animals Transgenic Model Transgenic Organisms Universities Withdrawal adenylyl cyclase 7 alcohol exposure behavior test drinking drinking behavior mRNA Differential Displays neuroadaptation preference programs protein expression protein profiling validation studies

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to alcohol results in neuroadaptive phenomena, including tolerance, sensitization, dependence, withdrawal, loss of control of drinking, and relapse that contribute to the development of excessive alcohol consumption. The goal of the INIA (Integrative Neuroscience Initiative on Alcoholism) Consortium is to identify the molecular, cellular, and behavioral neuroadaptations that occur in the brain reward circuits associated with the extended amygdala and its connections. It is hypothesized that genetic differences and/or neuroadaptations in this circuitry are responsible for the individual differences in vulnerability to the excessive consumption of alcohol. We propose to use quantitative proteomics to dissect the molecular mechanisms contributing to the behavioral phenotype of differential and excessive drinking (both baseline drinking and withdrawal induced drinking) in two animal models: 1) Adenylyl Cyclase 7 (AC7) transgenic animals - changes in the copy number of the AC7 gene produces changes in drinking phenotype using the Withdrawal Induced Drinking (WID) paradigm and 2) High Alcohol Preference (HAP)/Low Alcohol Preference (LAP) animals - animals selectively bred for differences in free-choice alcohol consumption by the 2 Bottle-Choice (2BC) paradigm - the selected genotype (changes in multiple genes) contributes to differential baseline drinking. Our goals are 1) to develop and optimize proteomic methodology for the quantitative analysis of enriched brain fractions, 2) to identify global differences in baseline protein expression between selected lines of the two animal models [AC7 transgenic model (AC7 transgenic versus wildtype) and HAP/LAP selective breeding model (HAP versus LAP)], and 3) to globally compare longitudinal changes in protein expression between animals (AC7 transgenic versus wildtype and HAP versus LAP) at selected time points during WID-2BC to identify proteins that contribute to the differential and excessive drinking behaviors.

描述（由申请人提供）：长期暴露于酒精会导致神经适应性现象，包括容忍，敏感性，依赖性，戒断，饮酒的控制丧失和复发，这导致过度酒精消耗的发展。 INIA（酒精中毒的综合神经科学倡议）的目标是确定在大脑奖励与扩展的杏仁核及其连接相关的大脑奖励电路中发生的分子，细胞和行为神经适应。假设该电路中的遗传差异和/或神经适应是导致过度消费饮酒的脆弱性的个体差异。我们建议使用定量蛋白质组学在两个动物模型中使用促成差异和过量饮酒的行为表型的分子机制（基线饮酒和戒断诱发的饮酒）：1）腺苷酸环化酶7（AC7）转基因动物的腺苷酸型（AC7）转移动物 - 使用AC7基因的繁殖量的变化（AC7基因的均值变化）（所指出的均变化）（所指出的均变化）（所指出的均变化）（HAP）/低酒精偏爱（圈）动物 - 动物选择性地育种，繁殖了2个瓶装选择（2BC）范式在自由选择酒精消耗中的差异 - 所选的基因型（多个基因的变化）有助于差异基线饮酒。我们的目标是1）开发和优化蛋白质组学方法论富集大脑分数的定量分析，2）确定基线的全球差异两种动物模型的选定线之间的蛋白质表达[AC7转基因模型（AC7）转基因与野生型）和HAP/LAP选择性育种模型（HAP与圈圈）和3）在WID-2BC上在wid-2BC上的动物（AC7转基因与野生型和HAP与HAP）之间的蛋白质表达的纵向变化，以比较对鉴定有助于差异和过度饮酒行为的蛋白质的纵向变化。