Biomarker Matrix for Genotoxicity Mode of Action

遗传毒性作用模式的生物标志物矩阵

基本信息

批准号：
8914767
负责人：
Jeffrey C Bemis
金额：
$ 49.29万
依托单位：
LITRON LABORATORIES, LTD.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914767
关键词：
ATM activation Address Animal Model Atherosclerosis Biological Assay Biological Markers Carcinogens Cell Cycle Cell Line Cell Nucleus Cells Chemicals Chromosome abnormality DNA DNA Damage DNA Single Strand Break DNA-PKcs Data Disease Exhibits Flow Cytometry Fluorescence Gene Mutation Genetic Goals Health Hereditary Disease Human In Vitro Incidence Kinetics Label Liver Logistic Regressions Mammalian Cell Measures Mediating Membrane Potentials Modeling Modification Mutagenicity Tests Performance Phase Plague Process Protocols documentation Rattus Reading Reagent Recovery Regression Analysis Risk Secondary to Sensitivity and Specificity Solutions Specificity Statistical Models Structure System Testing Toxic effect Toxicogenetics Training Treatment Protocols Validation Work base carcinogenesis clastogen cytotoxicity genotoxicity high throughput analysis in vivo method development micronucleus mitochondrial membrane predictive modeling preference product development prototype repaired research study response tool

项目摘要

DESCRIPTION (provided by applicant): It is well recognized that current batteries of genetic toxicology assays exhibit relatively high sensitivity, meaning they effectively identify genotoxic carcinogens. However, a critical deficiency with current approaches exists-namely, the specificity of the in vitro mammalian cell genotoxicity tests is low, as they yield a high incidenc of positive results that do not have in vivo relevance (so-called "misleading" or "irrelevant" positives). This high incidence of irrelevant in vitro positive results leads to extensive and costy additional testing, often with whole animal models, or else abandonment of potentially valuable products. We will address this major problem with current in vitro mammalian cell genetic toxicity assays by developing commercial kits that enable an automated testing strategy that exhibits both high sensitivity and specificity. This system will categorize positive results according to the predominant mode of genotoxic activity, and importantly, will reliably identify irrelevant mode(s) of action that are likely to be nonoperational in vivo. A secondary objective of the proposed work is the development of methods for characterizing clastogens. That is, we will develop tools that elucidate whether clastogenic activity is the result of DNA-reactivity, or whether it is mediated by an indirect mechanism.

描述（由申请人提供）：众所周知，目前的遗传毒理学检测组合表现出相对较高的灵敏度，这意味着它们可以有效地识别遗传毒性致癌物。然而，当前方法存在一个严重缺陷，即体外哺乳动物细胞遗传毒性测试的特异性较低，因为它们产生的阳性结果的发生率很高，但与体内不相关（所谓的“误导性”或“误导性”）。不相关”的积极因素）。这种不相关的体外阳性结果发生率很高，导致需要进行广泛且昂贵的额外测试，通常需要使用整个动物模型，否则就会放弃具有潜在价值的产品。我们将通过开发商业试剂盒来解决当前体外哺乳动物细胞遗传毒性测定的这一主要问题，该试剂盒能够实现具有高灵敏度和特异性的自动化测试策略。该系统将根据基因毒性活性的主要模式对阳性结果进行分类，重要的是，将可靠地识别可能在体内不起作用的不相关的作用模式。次要目标拟议的工作是开发表征断裂剂的方法。也就是说，我们将开发工具来阐明断裂活性是否是DNA反应的结果，或者是否是由间接机制介导的。