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Next Generation Testing Strategies for Assessment of Genotoxicity

下一代遗传毒性评估测试策略

基本信息

批准号：
9807074
负责人：
Jeffrey C Bemis
金额：
$ 48.23万
依托单位：
LITRON LABORATORIES, LTD.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807074
关键词：
Address Affect Aneugens Antioxidants Appearance Benchmarking Biological Assay Biological Markers Biological Response Modifiers Bleomycin Caspase Cell Cycle Cell Nucleus Cells Chemicals Chromosome abnormality Chromosomes Classification Cleaved cell Colcemid Companions Complex Computer Simulation DNA DNA Damage DNA Double Strand Break DNA Repair DNA-PKcs Data Data Analyses Data Set Disease Dose Epitopes Etoposide Exhibits Family GADD45A gene Gamma-H2AX Gene Mutation Genetic Goals Harvest Histone H3 Human In Vitro Intercalating Agents Investigation Kinetics Label Laboratories Logistic Regressions Machine Learning Malignant Neoplasms Mammalian Cell Methods Microtubules Modeling Modernization Modification Molecular Target Mutagenicity Tests NF-kappa B Nuclear Pathway interactions Phase Physiologic pulse Procedures Protocols documentation Reagent Reference Values Risk Assessment Schedule Scheme Series Stains TP53 gene Testing Time Toxic effect Toxicogenetics Training Validation Work aurora kinase base clastogen computerized tools design experimental study genotoxicity hazard inhibitor/antagonist next generation prediction algorithm prevent prototype random forest repaired response targeted agent tool treatment optimization virtual

项目摘要

Project Summary It is well recognized that current batteries of genetic toxicology assays exhibit two critical deficiencies. First, the throughput capacity of in vitro mammalian cell genotoxicity tests is low, and does not meet current needs. Second, conventional assays provide simplistic binary calls, genotoxic or non-genotoxic. In this scheme there is little or no consideration for potency, and virtually no information is provided about molecular targets and mechanisms. These deficiencies in hazard characterization prevent genotoxicity data from optimally contributing to modern risk assessments, where this information is essential. We will address these major problems with current in vitro mammalian cell genetic toxicity assays by developing methods and associated commercial assay kits that dramatically enhance throughput capacity, and delineate genotoxicants' primary molecular targets, while simultaneously providing information about potency. Once biomarkers and a family of multiplexed assays have been developed for these purposes, an interlaboratory trial will be performed with prototype assay kits to assess the transferability of the methods.

项目摘要众所周知，目前的遗传毒理学试验组表现出两个关键的缺陷。首先，体外哺乳动物细胞遗传毒性测试的通量能力低，并且不满足当前的要求。需求第二，常规测定提供简单的二进制调用，遗传毒性或非遗传毒性。在该方案中很少或根本没有考虑效力，实际上没有提供关于分子靶点的信息和机制。危害表征中的这些缺陷阻碍了遗传毒性数据的优化。为现代风险评估做出贡献，因为这一信息至关重要。我们将解决这些主要问题。通过开发方法和相关的方法来解决目前体外哺乳动物细胞遗传毒性测定的问题商业检测试剂盒，大大提高了通量能力，并描绘了遗传毒物的主要分子靶点，同时提供有关效力的信息。曾经的生物标志物和一个家族已开发了用于这些目的的多重测定，将进行实验室间试验，原型测定试剂盒，以评估方法的可转移性。