Modeling Lung Cancer in Telomerase Null Mice

描述（由申请人提供）： 肺癌是一个重大的国际健康问题。 仅在美国，估计2001年就有157，000人死于这种疾病，吸烟占所有肺癌的85%。 尽管最近在细胞毒性药物开发、放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，许多仍然未知的分子和遗传事件参与肺癌的发生和发展。 在上皮癌的发展中观察到的一个重要机制（即，肺癌）似乎是潜在的染色体不稳定性，这是由于在端粒酶活性不足的情况下，由于显著的细胞分裂而导致端粒功能丧失。 我们的实验室提出，年龄依赖性上皮更新，体细胞突变驱动克隆增殖和慢性损伤的组合可以加速端粒侵蚀，这最终导致染色体融合-桥-断裂-易位过程。 这个过程提供了一种机制，用于快速和大规模地改变细胞，罕见的细胞引起阈值数量的相关变化，以启动转换过程。 端粒酶的重新激活或替代端粒维持机制的上调使基因组重新稳定，允许此类起始细胞扩增并获得导致完全癌细胞的变化。 我建议建立在端粒酶缺陷小鼠的独特实验属性，以开发一种肺癌模型，该模型由人类肺癌发生的潜在机制驱动。 通过将端粒缩短的端粒酶缺陷小鼠暴露于慢性烟草烟雾，可以开发肺癌的生理小鼠模型：这将加速肺上皮细胞更新并促进全基因组诱变。 一旦验证，该模型将被用来研究端粒酶激活在肺癌发生过程中的作用，并作为新的肺癌基因发现的工具。 申请人是一名医学博士。在拟定的开始日期之前完成内科住院医师培训并接受成人医学肿瘤学亚专科培训。 他还拥有博士学位。在分子生物学和生物物理学中。 这项拟议中的研究将在达纳法伯癌症研究所的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.