ANDROGEN CONDITIONAL CARCINOGENESIS IN TRANSGENIC MICE

这项建议的长期目标是详细了解 控制细胞增殖的调控网络，这些网络如何 在肿瘤生长的启动和进展过程中受到干扰，以及 遗传因素是如何影响这些扰动的。为此， 建议的重点是分析转基因小鼠的肝脏肿瘤发生。 含小鼠主要尿蛋白(MUP)增强子/启动子融合 构造。明确的和相对较晚的出生后激活 肝脏中的这种启动子，以及潜在的雄激素条件 表达为肿瘤发生分析提供了一种新的方法。这些 转基因小鼠将被用来研究时间和阶段 肿瘤发生与癌基因表达的启动有关，是否 癌基因(转基因)的持续表达是必要的 肿瘤发生与肝脏基因表达变化的分析 在肝脏肿瘤发生的特定阶段。这项提案还将重点放在 影响易感性的遗传决定因素分析 自发的和化学诱导的肝癌发生以及是否 肝脏肿瘤发生的转基因模型对这些决定因素做出反应。

The long term goal of this proposal is to gain a detailed understanding of regulatory networks which control cell proliferation, how these networks are perturbed during initiation and progression of neoplastic growth, and how genetic factors influence these perturbations. To this end, the proposal is centered on analysis of liver tumorigenesis in transgenic mice containing mouse major urinary protein (MUP) enhancer/promoter fusion constructs. The well defined and relatively late postnatal activation of this promoter in the liver, and the potential androgen conditional expression provide a novel method for analysis of tumorigenesis. These transgenic mice will be used to investigate the timing and phasing of tumorigenesis relative to initiation of oncogene expression, whether continual expression of the oncogene (transgene) is necessary for tumorigenesis and analysis of changes in liver gene expression which occur during specific stages of liver tumorigenesis. This proposal also focuses on analysis of genetic determinants which influence susceptibility to spontaneous and chemically induced liver carcinogenesis and whether transgenic models of liver tumorigenesis respond to these determinants.