Modeling Lung Cancer in Telomerase Null Mice

描述(申请人提供)：肺癌是一个主要的国际健康问题。仅在美国，2001年估计将有15.7万人死于这种疾病，吸烟占所有肺癌的85%。尽管最近在细胞毒药物开发、放射治疗和外科治疗方面取得了进展，但晚期肺癌的治愈率仍然很低。此外，关于肺癌发生和发展所涉及的分子和遗传事件仍有许多未知之处。上皮性癌症(如肺癌)发生的一个重要机制是染色体不稳定，这是由于端粒酶活性不足的情况下细胞大量分裂导致的端粒功能丧失所致。我们的实验室提出，依赖年龄的上皮细胞更新、驱动克隆增殖的体细胞突变和慢性损伤的组合可以加速端粒侵蚀，最终导致染色体融合-桥-断裂-易位过程。这一过程为细胞的快速和大规模变化提供了一种机制，罕见的细胞会引起阈值数量的相关变化来启动转化过程。端粒酶的重新激活或替代的端粒维持机制的上调重新稳定了基因组，允许这种启动的细胞扩张并获得变化，导致完全癌变的细胞。 我建议在端粒酶缺陷小鼠独特的实验属性的基础上，开发一种由人类肺癌发生的潜在机制驱动的肺癌模型。通过将端粒缩短的端粒酶缺陷小鼠暴露在慢性烟草烟雾中，可以建立一种生理性的小鼠肺癌模型：这将加速肺上皮细胞的周转，促进全基因组的突变。一旦得到验证，这个模型将被用来检测端粒酶激活在癌症发生中的作用，并作为发现新的肺癌基因的工具。 申请人是医学博士，在建议的开始日期之前，他将完成内科住院医师资格，并接受成人肿瘤学专科培训。他还拥有分子生物学和生物物理学的博士学位。这项拟议的研究将在达纳·法伯癌症研究所罗纳德·德皮尼奥博士的实验室进行。

DESCRIPTION (provided by applicant): Lung cancer is a major international health problem. In the United States alone, an estimated 157,000 people will die of this disease in 2001 and tobacco use accounts for 85% of all lung cancers. Despite recent advances in cytotoxic drug development, radiotherapy and surgical management, the cure rate for advanced lung cancer remains poor. Further, much remains unknown about the molecular and genetic events involved in initiation and progression of lung cancer. One important mechanism seen in the development of epithelial cancers (i.e., lung cancer) appears to be underlying chromosomal instability due to a loss in telomere function brought about by significant cell division in the face of insufficient telomerase activity. Our laboratory has proposed that a combination of age-dependent epithelial renewal, somatic mutations that drive clonal proliferation, and chronic injury can accelerate telomere erosion, this culminating in a chromosomal fusion-bridge-breakage-translocation process. This process provides a mechanism for rapid and wholesale changes in cells, with rare cells incurring a threshold number of relevant changes to initiate the transformation process. Reactivation of telomerase or upregulation of alternative telomere maintenance mechanisms restabilizes the genome, allowing such initiated cells to expand and acquire changes resulting in a fully cancerous cell. I propose to build on the unique experimental attributes of the telomerase deficient mouse to develop a lung cancer model that is driven by mechanisms underlying the genesis of human lung cancer. A physiologic mouse model of lung cancer may be developed by exposing the telomerase deficient mice with shortened telomeres to chronic tobacco smoke: this will accelerate lung epithelial cell turnover and promote genome wide mutagenesis. Once validated, this model will be used to examine the role of telomerase activation during carcinogenesis, and as a tool for novel lung cancer gene discovery. The applicant is an M.D. who will have completed a residency in internal medicine with subspecialty training in adult medical oncology prior to the proposed start date. He also holds a Ph.D. in molecular biology and biophysics. The proposed research will be carried out in the laboratory of Dr. Ronald DePinho at the Dana Farber Cancer Institute.