Construction of Transgenic Telomerase Reporters

转基因端粒酶报告基因的构建

• 批准号: 7008819
• 负责人: JIYUE ZHU
• 金额: $ 18.45万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-18 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008819
• 关键词: DNA binding protein; RNA directed DNA polymerase; artificial chromosomes; bioimaging /biomedical imaging; bioluminescence; breast neoplasms; disease /disorder model; functional /structural genomics; genetic models; genetically modified animals; in situ hybridization; laboratory mouse; luciferin monooxygenase; method development; microinjections; model design /development; molecular cloning; neoplastic growth; polymerase chain reaction; telomerase

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.

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非侵入性成像方法可以对了解肿瘤发生和监测候选抗癌药物的功效的努力产生重要影响。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，并且已被提议作为癌症的诊断标志物。在这里，我们建议用小鼠和人类基因组 DNA 构建体生成转基因荧光素酶报告小鼠，用于监测体内 TERT 表达，这是端粒酶激活的限速步骤。我们的主要目标是测试使用此类报告基因作为成像标记来监测活体动物肿瘤进展的可行性。这些报告基因有可能用于对多种小鼠癌症模型中的肿瘤进行成像，并为临床前抗癌药物评估提供标准平台。此外，直接比较这些转基因报告小鼠中的小鼠和人类TERT启动子活性也可能揭示小鼠和人类端粒酶表达不同调节的分子机制。这种差异可能解释了一些人类癌症与其小鼠模型之间肿瘤谱的差异。