Predictive Genes Sets For Chemically-Induced Liver Cancer

描述（由申请人提供）： 根据目前的监管政策，被认为对人类构成重大接触和健康风险的化学品被选中进行毒性和致癌效力测试。 评价特定化学品致癌活性和慢性毒性的传统方法是两年生物测定法。由于涉及相对大量的资源，每个生物测定的成本在200万到400万美元之间，需要几年才能完成。根据国家毒理学计划（NTP），目前测试的化学品数量在长期研究中为505种，在短期测试中为66种，只有一项亚慢性研究。通过将已完成的生物测定数量与目前商业上的70，000至85，000种化学品进行比较，不可能将目前的测试系统应用于所有相关化学品。为了保护人类健康和节约经济资源，必须制定替代办法。为了开发一种有效和准确的评估未知化学品的致癌潜力，我们建议：（1）在使用组织工程啮齿动物肝脏模型的标准啮齿动物2年生物测定中鉴定一组预测化学诱导肝癌发生的基因;和（2）将来自啮齿动物研究的诊断基因表达谱应用于等同组织-工程人类肝脏模型，以评估化学诱导的致癌终点的跨物种缩放。为了实现这一点，将使用一组训练化合物进行体内暴露和工程三维肝脏共培养物的暴露，这些化合物包括以下类别的非肝癌原和肝癌原：遗传毒性、非遗传毒性、性别依赖性和物种依赖性。将对来自暴露动物和肝脏培养物的mRNA进行微阵列分析，并将结果用于鉴定在两年动物生物测定中统计学预测肝癌性的基因集。从这项研究中获得的商业产品将优先考虑未经测试的化学品的肝癌潜力，并为政府机构以及与化学品制造，食品添加剂和药品相关的私营行业节省大量时间，金钱和动物。

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.