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（AFT）是一种众所周知的现象，被认为会影响酗酒风险的个体差异，但 AFT 的潜在分子底物仍然是个谜。在此应用中，我们提议测试斑马鱼（Danio rerio）对乙醇产生的行为干扰表现出 AFT 的假设，该提议的主要目标是表征和开发斑马鱼作为研究中的模式生物。 AFT 的分子基础。斑马鱼为遗传学研究提供了许多优势，包括世代时间短、后代数量多、成本和空间需求低、斑马鱼遗传学信息不断增加，以及基因操作的简便性。斑马鱼在 AFT 研究中的另一个重要优势是，由于乙醇是通过与储存罐溶液平衡来施用的，因此可以轻松维持稳态血液和脑乙醇浓度；本质上，这是一个极其简单的乙醇夹。 AFT 的某些行为已在金鱼中得到证实，但尚未在斑马鱼中进行检验。该项目的具体目标是筛选几种已确定的斑马鱼获得 AFT 的行为，通过测试几种近交斑马鱼品系来确定 AFT 是否存在自然发生的遗传变异，并开发 AFT 的自动化、高通量诱变筛选方法。未来的研究将对大量诱变斑马鱼进行高通量筛选，目标是绘制斑马鱼 AFT 的分子基础。