Aneugen Screening in Optimized Yeast Strains

优化酵母菌株的 Aneugen 筛选

• 批准号: 6655611
• 负责人: Owen Hughes
• 金额: $ 34.91万
• 依托单位: EON CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655611
• 关键词: Saccharomyces cerevisiae; aneuploidy; carcinogen testing; drug metabolism; drug screening /evaluation; fluorimetry; genetic strain; membrane permeability; mutagen testing; technology /technique development; toxicology

DESCRIPTION (provided by applicant): Although aneuploidy is responsible for significant adverse human health conditions such as birth defects, mental retardation, spontaneous abortions, and cancer, little is known about the possible aneugenicity of the chemicals and drugs we are exposed to. In Phase I work, a novel Saccharomyces cerevisiae-based chomosome nondisjunction assay was developed for eventual use in high throughput screening. This nondisjunction assay has a simple fluorometric readout and responds to known aneugens. Here, the assay will be adapted to an economical high throughput format. In addition, methods for increasing the predictive value of yeast-based tests will be explored in two ways. First, methods for decreasing the pharmacokinetic differences between yeast and mammalian cells including 1) increasing drug uptake, 2) decreasing drug excretion, and 3) mimicking mammalian metabolism of test compounds will be explored. Second, two different types of "first hit" sensitizing mutations--centromere mutations and mitotic checkpoint mutations-- will be examined. Finally, the nondisjunction assay will be combined with a DEL-like assay to allow simultaneous assessment of both aneugenicity and carcinogenicity.

描述（由申请人提供）：尽管非整倍性是导致 严重不利的人类健康状况，例如出生缺陷、精神缺陷 发育迟缓、自然流产和癌症，但人们对这些疾病知之甚少 我们所接触的化学物质和药物可能存在非优生性。第一阶段 工作中，一种新型的基于酿酒酵母的染色体不分离测定法 开发用于最终用于高通量筛选。这种不分离 该测定具有简单的荧光读数并对已知的非优生物质做出反应。这里， 该测定将适应经济的高通量形式。此外， 提高基于酵母的测试的预测价值的方法将是 从两个方面进行探索。一、降低药代动力学的方法 酵母细胞和哺乳动物细胞之间的差异包括 1) 增加药物 吸收，2）减少药物排泄，3）模仿哺乳动物的代谢 将探索测试化合物。二、两种不同类型的“首击” 致敏突变——着丝粒突变和有丝分裂检查点突变—— 将接受检查。最后，非分离分析将与 类似 DEL 的检测可以同时评估非均质性和 致癌性。