Phenotype MicroArrays for Drug Toxicity Screening

用于药物毒性筛查的表型微阵列

基本信息

批准号：
6651478
负责人：
BARRY RONALD BOCHNER
金额：
$ 25万
依托单位：
BIOLOG, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-09 至 2004-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6651478
关键词：
cell line cellular respiration chemical structure function colorimetry drug adverse effect drug screening /evaluation high throughput technology microarray technology phenotype technology /technique development toxicology

项目摘要

DESCRIPTION (provided by applicant): Biolog has developed Phenotype MicroArrays (PMs) that can be employed as an in vitro screen for drug toxicity. This technology can measure thousands of physiological parameters of a cell in a simple-to-use HTS format. The core of the technology is a chemistry and image analysis system that detects changes in respiratory activity of cells grown under different physiological conditions. The changes in metabolic activity of the cell are measured as a colorimetric response detected with Biolog's automated OmniLog instrument. PMs allow for an information-rich colorimetric pattern to be generated for each drug and cell line examined. When a drug is tested in the PM, the colorimetric pattern changes and using pattern recognition technology, we can relate the color changes in the PM to the mode of action and side effects of the drug. The pattern is a fingerprint of that drug's action. When we test a large number of drugs with known pharmacological action, the individual fingerprints of each drug will have commonalities that will allow us to identify a reference standard for that class of pharmacological agents. A database of these signatures can be used to categorize novel compounds in a HTS program. Importantly, by testing drugs with well known in vivo toxicity, the fingerprints will have information about the toxicology of the drug tested and can be used to predict whether a drug "hit" will be toxic later on in development. In this Phase I SBIR grant, we propose to develop our PM technology into a HTS assay for drug toxicity. Two tissues which are most susceptible to drug toxicity are the liver and blood and these can serve as a good barometer for drug toxicity potential. In this grant we will optimize new prototype PMs and testing protocols for human liver and hematopoietic cell lines. We will then test a series of well-studied drugs that are structurally and mechanistically distinct but which have known toxicity and side effects in vivo. The profiles of metabolic activity generated by these drugs will be collated to generate a prototype of a database that can be used to screen small molecules for toxicity potential. In future studies (Phase II SBIR) we will expand the technology and scope of reference drugs tested to build a strong predictive database including cell lines representing more tissues and organs.

描述（由申请人提供）：生物学已经开发了表型微阵列（PMS），可以用作药物毒性的体外筛查。该技术可以以易于使用的HTS格式测量细胞的数千个生理参数。该技术的核心是一种化学和图像分析系统，该系统检测在不同生理条件下生长的细胞的呼吸活性变化。细胞的代谢活性的变化是用生物学的自动综合仪器检测到的比色响应的。 PMS允许为检查的每种药物和细胞系生成富含信息的比色模式。当在PM中测试药物时，比色模式会改变并使用模式识别技术，我们可以将PM的颜色变化与药物的作用方式和副作用联系起来。该模式是该药物作用的指纹。当我们通过已知的药理作用测试大量药物时，每种药物的个别指纹具有共同点，使我们能够确定该类别的药理学剂的参考标准。这些签名的数据库可用于对HTS程序中的新颖化合物进行分类。重要的是，通过测试具有众所周知的体内毒性的药物，指纹将具有有关已测试药物毒理学的信息，可用于预测药物“ hit”是否会在后来发育中有毒。在此阶段I SBIR赠款中，我们建议将我们的PM技术开发为HTS药物毒性分析。两种最容易受到药物毒性的组织是肝脏和血液，这些组织可以作为药物毒性潜力的良好晴雨表。在这笔赠款中，我们将优化针对人肝脏和造血细胞系的新的原型PMS和测试方案。然后，我们将测试一系列研究的药物，这些药物在结构和机械上是不同的，但在体内具有毒性和副作用。这些药物产生的代谢活性的特征将被整理成生成数据库的原型，该原型可用于筛选小分子的毒性潜力。在未来的研究（II阶段SBIR）中，我们将扩大经过测试的参考药物的技术和范围，以构建一个强大的预测数据库，包括代表更多组织和器官的细胞系。