Zebrafish model: molecular basis of acute EtOH tolerance

斑马鱼模型：急性乙醇耐受的分子基础

• 批准号: 6779660
• 负责人: RICHARD A RADCLIFFE
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779660
• 关键词: alcoholism /alcohol abuse; alternatives to animals in research; behavior test; behavioral /social science research tag; behavioral genetics; biomedical automation; digital imaging; drug administration rate /duration; drug tolerance; ethanol; ethology; genetic screening; high throughput technology; method development; model design /development; pharmacogenetics; substance abuse related behavior; zebrafish

DESCRIPTION (provided by applicant): Acute functional tolerance (AFT) to ethanol is a well known phenomenon that is thought to influence individual differences in risk liability for alcoholism, but the underlying molecular substrates of AFT remain a mystery. In this application, we are proposing to test the hypothesis that the zebrafish (Danio rerio) will exhibit AFT to the behavioral disruptions produced by ethanol, with the main goal of the proposal to characterize and develop the zebrafish as a model organism in the study of the molecular basis of AFT. Zebrafish provide numerous advantages for genetic studies including short generation time, large numbers of offspring, low cost and space demands, a growing body of information on the genetics of zebrafish, and the ease with which genetic manipulations can be accomplished. Another important advantage of zebrafish in AFT studies is that a steady-state blood and brain ethanol concentration can easily be maintained since the ethanol is administered via equilibration with the holding tank solution; in essence, an extremely simple ethanol clamp. AFT for certain behaviors has been demonstrated in goldfish, but it has not been examined in zebrafish. The Specific Aims of this project are to screen several established zebrafish behaviors for the acquisition of AFT, determine if there is naturally occurring genetic variation for AFT by testing several inbred zebrafish strains, and to develop methods for automated, high-throughput mutagenesis screens for AFT. Future studies will implement the high-throughput screens on large numbers of mutagenized zebrafish with the goal of mapping the molecular basis of AFT in zebrafish.

描述（由申请人提供）：对乙醇的急性功能耐受性（AFT）是一种众所周知的现象，被认为会影响酒精中毒风险责任的个体差异，但后后的基本分子基板仍然是一个谜。在此应用中，我们提议检验以下假设：斑马鱼（Danio rerio）将表现出乙醇所产生的行为破坏，其主要目标是将斑马鱼作为模型的有机体在AFT的分子基础研究中表征和发展为模型的生物体。斑马鱼为遗传研究提供了许多优势，包括短期，大量后代，低成本和空间需求，越来越多的有关斑马鱼遗传学的信息以及可以实现遗传操作的容易性。斑马鱼在AFT研究中的另一个重要优势是，由于乙醇是通过用固定罐溶液平衡给药的，因此可以轻松保持稳态的血液和脑乙醇浓度。本质上，这是一个非常简单的乙醇夹。在金鱼中已经证明了某些行为的船尾，但尚未在斑马鱼中进行检查。该项目的具体目的是通过测试几种近交斑马鱼菌株来筛选出几种已建立的斑马鱼行为，以确定AFT的天然遗传变异，并开发用于自动化，高通量诱变的方法的方法。未来的研究将在大量诱变斑马鱼上实施高通量屏幕，目的是绘制斑马鱼Aft的分子基础。