SENSITIVE TRANSGENIC MODEL FOR CARCINOGEN DETECTION

用于致癌物检测的敏感转基因模型

• 批准号: 2712957
• 负责人: LEILA DIAMOND
• 金额: $ 10万
• 依托单位: CANCER PREVENTION GENETICS, INC..
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2712957
• 关键词: DNA damage; benzanthracenes; cancer risk; carcinogen testing; disease /disorder model; dosage; genetically modified animals; histopathology; laboratory mouse; model design /development; neoplastic transformation; ornithine decarboxylase; skin neoplasms

In this application, it is proposed to validate a unique transgenic mouse model for identification of genotoxic carcinogens. The mice have been engineered to overexpress the enzyme ornithine decarboxylase (ODC) in skin and other tissues. As a result, the mice are endogenously "promoted" and thus very sensitive for tumor induction to very low, initiating doses of known skin carcinogens. The model will be further validated by conducting dose-response studies for several carcinogenic and noncarcinogenic compounds. The sensitivity of the upper aerodigestive tract to a known carcinogen will also be evaluated in this model. The potential for technological innovation in this application is the likelihood that, for the first time, a short-term, highly sensitive and inexpensive in vivo model will be available to test suspect chemicals at low doses, more relevant to typical human exposures than the maximum tolerated doses commonly employed in current test systems. In terms of chemical risk assessment, it could be feasible using results from this model to base regulatory decisions on low dose data, rather than have to extrapolate from high dose data as is currently done. PROPOSED COMMERCIAL APPLICATIONS An in vivo model will be developed for testing the carcinogenic potential of drugs, environmental chemicals, and dietary constituents. Because the model is extremely sensitive, chemicals can be tested at low doses, comparable to human exposure levels.

在本申请中，建议验证一种独特的转基因小鼠 遗传毒性致癌物的鉴定模型。这些老鼠 工程化以过表达酶鸟氨酸脱羧酶（ODC）， 皮肤和其他组织。于是，老鼠们被内源性地“晋升”了 因此对肿瘤诱导非常敏感，起始剂量非常低， 已知的皮肤致癌物。该模型将进一步验证， 对几种致癌物质进行剂量反应研究， 非致癌化合物。上呼吸消化道的敏感性 也将在该模型中评估已知致癌物的途径。的 技术创新的潜力在这一应用是 可能性，第一次，一个短期的，高度敏感和 廉价的体内模型将可用于测试可疑的化学品， 低剂量，比最大剂量与典型的人类接触更相关 目前试验系统中常用的耐受剂量。方面 化学品风险评估，它可能是可行的，使用的结果，从这个 根据低剂量数据制定监管决策，而不是必须 如目前所做的那样，从高剂量数据进行推断。 建议的商业应用 将开发体内模型以测试致癌潜力 药物、环境化学品和饮食成分的影响。因为 模型非常敏感，化学品可以在低剂量下进行测试， 与人体暴露水平相当。