Construction of Transgenic Telomerase Reporters

描述（由申请人提供）：允许在小鼠模型中跟踪肿瘤发生和癌症进展的关键步骤的无创成像方法可以对了解肿瘤发生和监测抗癌候选药物的功效产生重要影响。端粒酶激活发生在超过90%的人类癌症以及小鼠癌症模型中，并且已被提出作为癌症的诊断标记。在这里，我们提出用小鼠和人类基因组DNA构建转基因荧光素酶报告小鼠，用于监测体内TERT的表达，这是端粒酶激活的限速步骤。我们的主要目的是测试使用这些报告基因作为成像标记物来监测活体动物肿瘤进展的可行性。这些报告基因可以潜在地用于在广泛的小鼠癌症模型中成像肿瘤，并为临床前抗癌药物评估提供标准平台。此外，直接比较小鼠和人TERT启动子在这些转基因报告小鼠中的活性也可能揭示小鼠和人端粒酶表达不同调控的分子机制。这种差异可能解释了某些人类癌症和小鼠模型之间肿瘤谱的差异。

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.