In Vivo Discovery of Psychotropic Drugs by High-Throughput Behavioral Phenotyping

通过高通量行为表型分析体内发现精神药物

基本信息

批准号：
7725787
负责人：
RANDALL T PETERSON
金额：
$ 35.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-02 至 2013-04-30
项目状态：
已结题

项目摘要

In vivo discovery of psychotropic drugs by high-throughput behavioral phenotyping the challenge despite their ubiquity and impact, diseases of the central nervous system (CNS) remain among the most poorly treated medical conditions. New CNS drugs are needed, but the complexity of the nervous system has largely made CNS drug discovery refractory to reductionist and in vitro approaches. For this reason, most existing CNS drugs were discovered by serendipitous observation of behavioral effects in living animals, not by rational design or in vitro screening. Discovering new CNS drugs is limited by the difficulty of modeling complex brain function in vitro and the impracticality of screening for new drugs in vivo with existing mammalian behavioral assays. Our approach we propose to use high-throughput behavioral assays as a means of screening for novel neuroactive drugs. We are developing fully-automated systems capable of tracking and quantifying zebrafish behaviors in high- throughput, 96-well format. Using one of these assays, we have tested 700 psychotropic drugs from several functional classes and identified strong correlations between specific functional classes and the zebrafish behavioral profiles they induce. We now propose to expand the panel of automated behavioral assays and conduct screens of vast small molecule libraries to identify novel compounds with in vivo neurological activity. The potential impact the automated panel of zebrafish assays we are developing is the first high-throughput screen capable of assessing behavioral effects of small molecules in a vertebrate. Because the zebrafish behaviors integrate inputs from several major neurotransmitter systems, the assays can be used to identify compounds that act on the CNS through diverse mechanisms. Successful completion of this project will create a robust and flexible system for discovering neuroactive compounds. It will also lead directly to discovery of novel compounds that alter CNS function through diverse mechanisms of action. These compounds will be powerful tools for studying the nervous system and in some cases may be developed further for treating nervous system disorders. Nervous system disorders like schizophrenia and Alzheimer's disease are widespread and frequently devastating, but they remain poorly treated because conventional drug discovery methods are poorly equipped to deal with the complexity of the brain. This project proposes a bold new approach to nervous system drug discovery based on robotic testing of thousands of potential new drugs for their ability to alter brain function in microscopic zebrafish.

在体内发现精神药物通过高通量的行为表型来挑战，尽管它们无处不在和影响，但中枢神经系统（CNS）的疾病仍然是治疗良好的医疗状况之一。需要新的中枢神经系统药物，但是神经系统的复杂性在很大程度上使CNS药物发现难治性对还原主义和体外方法。因此，大多数现有的中枢神经系统药物是通过对活动物中行为效应的偶然性观察而不是通过理性设计或体外筛查发现的。发现新的CNS药物受到对体外复杂大脑功能进行建模的困难以及现有哺乳动物行为分析的新药物筛查的不切实际性的限制。我们建议使用高通量行为测定作为筛查新型神经活性药物的一种手段。我们正在开发能够以96孔格式跟踪和量化斑马鱼行为的完全自动化系统。使用其中一种测定方法，我们已经测试了来自几个功能类别的700种精神药物，并确定了特定功能类别与它们引起的斑马鱼行为曲线之间的牢固相关性。现在，我们建议扩大自动行为分析的小组，并进行庞大的小分子文库的筛选，以鉴定具有体内神经活性的新型化合物。我们正在开发的斑马鱼测定法的潜在影响是第一个能够评估脊椎动物中小分子行为效应的高通量屏幕。由于斑马鱼行为整合了几个主要神经递质系统的输入，因此可以使用这些测定方法来识别通过各种机制对CNS作用的化合物。该项目的成功完成将创建一个强大而灵活的系统，用于发现神经活性化合物。它还将直接导致发现新型化合物，这些化合物通过各种作用机理改变CNS功能。这些化合物将是研究神经系统的强大工具，在某些情况下可能会进一步开发用于治疗神经系统疾病。精神分裂症和阿尔茨海默氏病等神经系统疾病广泛并且经常造成毁灭性，但由于常规的药物发现方法无法处理大脑的复杂性，因此它们的治疗仍然很差。该项目提出了一种基于数千种潜在的新药的机器人测试，以改变微观斑马鱼的大脑功能的能力，提出了一种大胆的神经系统药物发现方法。