Phenotype MicroArrays for Drug Toxicity Screening

用于药物毒性筛查的表型微阵列

• 批准号: 7110305
• 负责人: BARRY RONALD BOCHNER
• 金额: $ 69.25万
• 依托单位: BIOLOG, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-09 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110305
• 关键词: biotechnology; cancer information system; cell growth regulation; cell line; cellular respiration; colorimetry; drug adverse effect; drug discovery /isolation; drug screening /evaluation; high throughput technology; liver cells; metabolism; microarray technology; molecular biology information system; phenotype; technology /technique development; tissue /cell culture; toxicant screening; toxicology information system; biotechnology; cancer information system; cell growth regulation; cell line; cellular respiration; colorimetry; drug adverse effect; drug discovery /isolation; drug screening /evaluation; high throughput technology; liver cells; metabolism; microarray technology; molecular biology information system; phenotype; technology /technique development; tissue /cell culture; toxicant screening; toxicology information system

DESCRIPTION (provided by applicant): In this Phase II SBIR grant, we propose to develop our Phenotype MicroArray (PM) technology into a high throughput screening (HTS) assay for drug toxicity. The proposal addresses a key need in drug discovery for faster, simpler, and less expensive technologies that can assess drug candidates for potential toxicology as well as mechanism of action. Biolog has developed a prototype technology that can be employed for in vitro screening of drug toxicity. It is designed to work with human cell lines selected to represent the different organs and tissues where toxicity is typically exhibited. The 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 cultured 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. A unique aspect of this cell-based approach to toxicological testing is that we can see the effect of the drug on cells under nearly 2000 diverse physiological states of the cell. Alternative methods of testing cells or animals only test for toxicology in a healthy and proliferative state. Another unique aspect is that the technology also tests drug combinations and can provide highly useful synergy and antagonism information. In Phase II of this project we propose to expand the set of PM tests that can be performed from the current set of 600 to approximately 2000, miniaturize and automate the technology, and then construct an initial database of chemical fingerprints by testing 2000 chemicals of known classes and toxicities. In addition to applications in toxicology, this technology will be useful in basic research to study cell biology, metabolic diseases, and gene function, and in applied cell biology for QC testing of cell lines and bioprocess development.

描述（由申请人提供）：在此II阶段SBIR赠款中，我们建议将表型微阵列（PM）技术开发为高通量筛查（HTS）的药物毒性测定法。该提案针对发现药物发现的关键需求，以更快，更简单，更便宜的技术可以评估候选药物的潜在毒理学和作用机理。 Biolog开发了一种原型技术，可用于在药物毒性的体外筛查中。它旨在与选择的人类细胞系一起使用，以表示通常显示毒性的不同器官和组织。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培养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。这种基于细胞的毒理学测试方法的一个独特方面是，我们可以看到该药物对细胞近2000种不同生理状态下细胞的影响。测试细胞或动物的替代方法仅在健康和增殖状态下测试毒理学。另一个独特的方面是，该技术还可以测试药物组合，并可以提供非常有用的协同和对抗信息。在该项目的第二阶段中，我们建议将可以从当前600组进行的PM测试集进行扩展到大约2000年，将技术化和自动化技术，然后通过测试2000种已知类别和毒性的化学品来构建一个化学指纹的初始数据库。除了在毒理学中的应用外，该技术还将在研究细胞生物学，代谢疾病和基因功能以及应用细胞生物学中用于细胞系和生物过程开发的应用细胞生物学。