Modeling Lung Cancer in Telomerase Null Mice

描述（申请人提供）：肺癌是一个重大的国际健康问题。仅在美国，估计2001年将有15.7万人死于这种疾病，烟草使用占所有肺癌的85%。尽管最近在细胞毒性药物开发、放射治疗和手术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的分子和遗传事件仍有许多未知之处。在上皮性癌症（即肺癌）的发展中，一个重要的机制似乎是由于端粒酶活性不足时细胞分裂导致端粒功能丧失而导致的潜在染色体不稳定。我们的实验室提出，年龄依赖性上皮更新、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，罕见的细胞会产生一定数量的相关变化，从而启动转化过程。端粒酶的再激活或另一种端粒维持机制的上调使基因组重新稳定，允许这些初始细胞扩展并获得导致完全癌细胞的变化。

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.