Evaluation of Selected Transgenic Mouse Models as Altern

选定的转基因小鼠模型作为替代品的评估

• 批准号: 6543015
• 负责人: Raymond W Tennant
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6543015
• 关键词: bioassay; cancer risk; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical structure function; disease /disorder model; disease /disorder proneness /risk; environmental exposure; environmental toxicology; genetically modified animals; laboratory mouse; model design /development; mutagen testing; neoplasm /cancer; neoplasm /cancer genetics; tumor suppressor genes

We are bringing to culmination several years effort to develop and evaluate alternative short-term models for identifying potential environmental carcinogens based upon the use of genetically modified mouse lines. The hypothesis underlying this work was that introduction or alteration of selected genes known to be involved in critical pathways of tumorigenicity could result in a truncation of the neoplastic process when such animals were exposed to chemicals. The principle models focus upon in this laboratory were the p53 deficient line and a v-Ha-ras zetaglobin promoted line (Tg.AC). The results of work published from our studies have helped to catalyze an international effort to evaluate these and other short-term models that was organized by the International Life Sciences Institute and involved over 50 organizations representing private sector pharmaceutical and chemical companies, and government research and regulatory agencies. The culmination of this project has verified the value of selected transgenic models and has resulted in the implementation of the use of the models, particularly within the US pharmaceutical industry under the guidance of the Food and Drug Administration. In addition, we have proposed a strategy through which transgenic models could be implemented in conventional carcinogenicity studies during the subchronic toxicological characterization of chemicals that would result in informative data being available that could preclude the necessity to conduct a long-term two year bioassay or to be able to modify the conduct of long-term studies. This would result in reducing costs, decreasing the time in which the chemical is characterized and in reducing the number of animals necessary to characterize the toxicologic in carcinogenic properties of chemicals.

几年来，我们一直在努力开发和评估替代性短期模型，以确定基于转基因小鼠品系的潜在环境致癌物。这项工作的基本假设是，当这些动物暴露于化学品时，已知参与致瘤性关键途径的选定基因的引入或改变可能导致肿瘤过程的截断。本实验室关注的主要模型是p53缺陷系和v-Ha-ras zetaglobin促进系（Tg.AC）。我们研究发表的工作结果有助于催化国际社会评估这些模型和其他短期模型的努力，该努力由国际生命科学研究所组织，涉及代表私营部门制药和化学公司以及政府研究的50多个组织和监管机构。这一项目的最终结果证实了选定的转基因模型的价值，并导致了这些模型的使用，特别是在美国食品和药物管理局的指导下，在美国制药行业内。此外，我们提出了一种策略，通过该策略，在化学品的亚慢性毒理学表征期间，可以在常规致癌性研究中实施转基因模型，从而获得信息数据，从而可以排除进行长期两年生物测定的必要性或能够修改长期研究的实施。这将导致降低成本，减少表征化学品的时间，并减少表征化学品的毒理学或致癌特性所需的动物数量。