Predictive Genes Sets For Chemically-Induced Liver Cancer

化学诱导肝癌的预测基因组

• 批准号: 7290454
• 负责人: Brian A Naughton
• 金额: $ 65万
• 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/7290454
• 关键词: Animal Testing; Animals; Aryl Hydrocarbon Receptor; Biochemical; Biological Assay; Canis familiaris; Cell Survival; Chemical Exposure; Chemicals; Chronic; Class; Classification; Coculture Techniques; Commerce; Diagnostic; Economics; Elements; End Point; Engineering; Environment; Exposure to; Food Additives; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Growth; Health; Health Policy; Hepatocarcinogenesis; Homeostasis; Human; Hypoxia; Industry; Inflammatory Response; Liver; Longitudinal Studies; Maintenance; Malignant neoplasm of liver; Messenger RNA; Metabolic; Metabolic Activation; Methodology; Methods; Microarray Analysis; Modeling; Molecular Profiling; Mus; National Toxicology Program; Nature; Numbers; Outcome; Peroxisome Proliferator-Activated Receptors; Pharmacologic Substance; Phase; Phenotype; Policies; Population; Property; Protein Secretion; Public Health; Rattus; Research; Resources; Risk; Rodent; Role; Savings; Science; Signal Transduction Pathway; Standards of Weights and Measures; System; Testing; Thinking; Time; Tissue Engineering; Tissue Viability; Tissues; Today; Toxic effect; Toxicity Tests; Training; United States Food and Drug Administration; Work; base; cell type; constitutive androstane receptor; cost; enzyme activity; expectation; exposed human population; hepatotoxin; in vivo; interest; miniaturize; response; sex; toxicant

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）： 根据现行监管政策，选择对人类构成重大暴露和健康风险的化学物质进行毒性和致癌性测试。 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生物测定。由于涉及的资源相对较多，每次生物测定的成本在200万至400万美元之间，并且需要数年时间才能完成。根据国家毒理学计划 (NTP) 的数据，目前长期研究测试的化学品数量为 505 种，短期测试的化学品数量为 66 种，而且只有一项亚慢性研究。通过将已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，不可能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，必须制定替代方法。为了对未知化学物质的致癌潜力进行有效、准确的评估，我们建议：(1) 使用组织工程啮齿动物肝脏模型，在标准啮齿动物 2 年生物测定中鉴定一组可预测化学诱导肝癌发生的基因; (2) 将啮齿动物研究得出的诊断基因表达谱应用于等效的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尺度。为了实现这一目标，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物质和肝癌物质：基因毒性、非基因毒性、性别依赖性和物种-依赖。将对来自暴露的动物和肝脏培养物的 mRNA 进行微阵列分析，并将结果用于识别在两年的动物生物测定中统计预测肝癌性的基因组。来自这项研究的商业产品将能够优先考虑未经测试的化学品的潜在肝癌可能性，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。