Construction of Transgenic Telomerase Reporters

描述(由申请人提供)：非侵入性成像方法可以跟踪小鼠模型中肿瘤发生和癌症进展的关键步骤，这对了解肿瘤发生和监测抗癌候选药物的疗效具有重要影响。端粒酶的激活存在于90%以上的人类癌症和小鼠癌症模型中，并被认为是癌症的诊断标志。在这里，我们建议用鼠和人的基因组DNA构建转基因荧光素酶报告鼠来监测体内TERT的表达，TERT是端粒酶激活的限速步骤。我们的主要目标是测试使用这样的记者作为成像标记物来监测活体动物肿瘤进展的可行性。这些记者可能被用来对广泛的小鼠癌症模型中的肿瘤进行成像，并为临床前抗癌药物的评估提供一个标准平台。此外，在这些转基因报告鼠中直接比较小鼠和人类TERT启动子的活性也可能揭示小鼠和人类端粒酶表达调控不同的分子机制。这种差异可能解释了一些人类癌症和它们的小鼠模型之间的肿瘤光谱差异。

DESCRIPTION (provided by applicant): Noninvasive imaging methods that allow the tracking of critical steps in tumorigenesis and cancer progression in mouse models can impact importantly on efforts to understand tumorigenesis and to monitor the efficacy of anticancer drug candidates. Telomerase activation occurs in over 90% of human cancers as well as in mouse cancer models, and has been proposed be a diagnostic marker for cancer. Here, we propose to generate transgenic luciferase reporter mice with mouse and human genomic DNA constructs for monitoring the in vivo TERT expression, the rate-limiting step of telomerase activation. Our primary objective is to test the feasibility of using such reporters as imaging markers to monitor tumor progression in live animals. These reporters can potentially be used to image tumors in a broad spectrum of mouse cancer models and provide a standard platform for pre-clinical anticancer drug evaluation. In addition, direct comparison of mouse and human TERT promoter activities in these transgenic reporter mice may also reveal the molecular mechanisms underlying the different regulation of telomerase expression in mice and humans. Such difference may account for the discrepancies in tumor spectra between some human cancers and their mouse models.