Predictive Genes Sets For Chemically-Induced Liver Canc*

化学诱发肝癌的预测基因组*

• 批准号: 7288482
• 负责人: Brian A Naughton
• 金额: $ 63.64万
• 依托单位: REGENEMED, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7288482
• 关键词: aromatic hydrocarbon receptor; bioassay; biological signal transduction; carcinogen testing; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; clinical research; enzyme activity; enzyme linked immunosorbent assay; gene expression profiling; glutathione transferase; hypoxia; laboratory rat; liver neoplasms; messenger RNA; microarray technology; peroxisome proliferator activated receptor; technology /technique development; toxicology

DESCRIPTION (provided by applicant): Under current regulatory policies, chemicals that are believed to comprise both a significant exposure and health risk in the human population are selected to undergo testing for toxicity and carcinogenic potency. The traditional method for evaluating carcinogenic activity and chronic toxicity of a specific chemical has been the two-year bioassay. Due to relatively large amounts of resources involved, each bioassay costs between 2 million and 4 million dollars and takes several years to complete. According to the National Toxicology Program (NTP), the number of chemicals currently tested stands at 505 in long-term studies and 66 in short-term tests, and only a single sub-chronic study. By comparing the number of completed bioassays with the 70,000 to 85,000 chemicals in commerce today it is impossible to apply the current testing system to all chemicals of concern. Alternative approaches must be developed in the interest of protecting human health and in saving economic resources. To develop an efficient and accurate assessment of the carcinogenic potential of an unknown chemical we propose to: (1) identify a set of genes that is predictive of chemically induced hepatocarcinogenesis in a standard rodent 2-year bioassay using a tissue-engineered rodent liver model; and (2) apply the diagnostic gene expression profile derived from the rodent studies to the equivalent tissue-engineered human liver model to evaluate cross-species scaling of the chemically-induced carcinogenic endpoint. To accomplish this, in vivo exposures and exposures of engineered three-dimensional liver co-cultures will be performed with a training set of compounds that include non-hepatocarcinogens and hepatocarcinogens of the following classes: genotoxic, non-genotoxic, sex-dependent and species-dependent. Microarray analysis will be performed on mRNA derived from the exposed animal and liver cultures and the results used to identify gene sets that are statistically predictive of hepatocarcinogenicity in the two-year animal bioassay. A commercial product derived from this research will enable prioritization of hepatocarcinogenic potential of untested chemicals and allow a significant savings of time, money and animals for both governmental agencies as well as private industry related to chemical manufacturing, food additives and pharmaceuticals.

描述（由申请人提供）： 在当前的监管政策下，被认为既包含人口的重大暴露和健康风险的化学物质，以进行毒性和致癌效力的测试。 评估特定化学物质的致癌活性和慢性毒性的传统方法是两年的生物测定方法。由于涉及的资源相对较大，每个生物测定费用在200万至400万美元之间，需要几年的时间才能完成。根据国家毒理学计划（NTP），在长期研究中，目前已测试的化学物质数量为505，在短期测试中为66个，只有一项亚基核研究。通过将完成的生物测定数量与当今商业中的70,000至85,000种化学品进行比较，就无法将当前的测试系统应用于所有关注的化学品。为了保护人类健康和节省经济资源，必须开发出替代方法。为了对未知化学物质的致癌潜力进行有效，准确的评估：（1）确定一组基因，可以使用组织工程学的啮齿动物肝模型在标准啮齿动物的2年生物测定中预测化学诱导的肝癌发生； （2）将从啮齿动物研究得出的诊断基因表达谱应用于等效组织工程的人肝模型，以评估化学诱导的致癌终点的跨物种缩放。为此，将使用包括非肝癌剂和肝癌的训练组进行体内暴露和工程三维肝共培养的暴露：遗传毒性，非基因毒性，非基因毒性，性别依赖性和依赖性和依赖性。微阵列分析将对源自暴露的动物和肝脏培养物衍生的mRNA进行，并用于鉴定在两年的动物生物测定中统计上预测肝癌的基因集。从这项研究中得出的商业产品将优先考虑未经测试的化学物质的肝癌潜力，并为政府机构以及与化学制造，食品添加剂和药品有关的私营企业提供大量的时间，金钱和动物。