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）：允许跟踪小鼠模型中肿瘤发生和癌症进展中关键步骤的非侵入性成像方法可以对理解肿瘤发生的努力产生重要影响，并监测抗癌药物候选药物的功效。端粒酶激活发生在超过90％的人类癌症和小鼠癌模型中，并已被提议成为癌症的诊断标记。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基因小鼠，以监测体内TERT表达，这是端粒酶激活的速率限制步骤。我们的主要目的是测试使用像成像标记那样的记者监测活动物肿瘤进展的可行性。这些记者可以可能用于在各种小鼠癌模型中对肿瘤进行成像，并为临床前抗癌药物评估提供标准平台。此外，这些转基因报道小鼠中小鼠和人类TERT启动子活性的直接比较也可能揭示了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某些人类癌症及其小鼠模型之间肿瘤光谱的差异。