Profiles of Sucsceptibility to Toxicant Stress

描述（由申请人提供） 北卡罗来纳大学查珀尔分校的毒理基因组学研究项目 Hill（UNC-CH）的研究重点是易感性的遗传决定因素， 环境毒物和化疗药物。人和鼠模型 系统将用于确定基因变异的模式 当细胞和动物暴露于几类毒素时， 正在研究的毒素类别包括诱导氧化应激的物质，DNA 双链断裂，DNA碱基的烷基化，以及核受体 激动剂包含超过10，000个表达基因的cDNA微阵列 将用于确定人类细胞和小鼠的剂量和时间动力学 毒素引起的基因表达变化的证据在两项互动研究中， 投射二倍体人乳腺上皮细胞、成纤维细胞和成淋巴细胞， 将被用大约平均致死剂量的毒物处理 （D/o用于菌落形成灭活）。具有杂合和 肿瘤抑制基因p53、ATM和BRCA 1的纯合突变，或 基因失活的抑制功能，将比较野生型 品系，以建立对毒物胁迫的遗传易感性谱。 同样，第三个研究项目将确定对 对10个品系小鼠的肝、乳腺和结肠中的毒物进行了测定 不同的致癌可能性。这些研究将决定 小鼠品系依赖的致癌易感性是否类似于 肿瘤抑制基因突变导致的人类遗传易感性。一 毒理学资源核心提出了一个示范项目，以确定 暴露于非遗传毒性物质的小鼠肝脏中改变的基因表达谱 激活核受体AhR、CAR和PPAR-alpha的化学物质。的 三个研究项目和毒理学资源核心将由一个 管理核心、微阵列设施核心和信息设施 核心UNC-CH毒理基因组学研究计划拥有科学专业知识， 和组织基础设施，以提供重要的和实质性的 毒理基因组学研究联盟的利益。

DESCRIPTION (provided by applicant) The toxicogenomics research program at the University of North Carolina-Chapel Hill (UNC-CH) is focused on genetic determinants of susceptibility to environmental toxicants and chemotherapeutic drugs. Human and murine model systems will be used to determine the patterns of alterations in gene expression when cells and animals are exposed to several classes of toxins. Toxin classes under study include agents that induce oxidative stress, DNA double strand breaks, alkylation of DNA bases, as well as nuclear receptor agonists. cDNA microarrays containing greater than 10,000 expressed genes will be used to determine for human cells and mice, the dose and time kinetics of toxicant-induced changes in gene expression. In two interactive research projects diploid human mammary epithelial cells, fibroblasts and lymphoblasts, will be treated with doses of toxicants ranging about the mean lethal dose (D/o for inactivation of colony formation). Cell lines with heterozygous and homozygous mutations in the tumor suppressor genes p53, ATM and BRCA1, or with genetic inactivation of suppressor function, will be compared to wildtype lines to establish profiles of genetic susceptibility to toxicant stress. Similarly, a third research project will determine patterns of response to the toxicants in liver, mammary gland and colon of ten strains of mice with varying susceptibilities to carcinogenesis. These studies will determine whether murine strain-dependent susceptibility to carcinogenesis resembles human genetic susceptibility due to mutations in tumor suppressors. A Toxicology Resource Core proposes a demonstration project to determine the profiles of altered gene expression in livers of mice exposed to non-genotoxic chemicals which activate the nuclear receptors, AhR, CAR and PPAR-alpha. The three research projects and the Toxicology Resource Core will be served by an Administrative Core, a Microarray Facility Core, and an lnformatics Facility Core. The UNC-CH toxicogenomics research program has the scientific expertise and organizational infrastructure to provide significant and substantial benefits to the Toxicogenomics Research Consortium.