ANDROGEN CONDITIONAL CARCINOGENESIS IN TRANSGENIC MICE

本提案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 在肿瘤生长的开始和进展期间受到干扰，并且 遗传因素如何影响这些扰动。 为此中央 一项提案集中于分析转基因小鼠的肝肿瘤发生 含有小鼠主要尿蛋白（MUP）增强子/启动子融合体 结构。 明确的和相对较晚的出生后激活， 这种启动子在肝脏中，和潜在的雄激素条件 表达为分析肿瘤发生提供了新的方法。 这些 转基因小鼠将被用于调查的时间和阶段， 与癌基因表达起始相关的肿瘤发生， 癌基因（转基因）的持续表达是必要的， 肿瘤发生和分析肝脏基因表达的变化， 在肝脏肿瘤发生的特定阶段。 该提案还重点 分析影响易感性的遗传决定因素， 自发和化学诱导的肝癌发生， 肝肿瘤发生的转基因模型对这些决定因素有反应。

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.