Establishment and Characterisation of Mouse Models for Colorectal Carcinoma

肠癌是西方国家最常见的肿瘤之一。结肠癌的发生过程涉及细胞信号级联的逐步、渐进的破坏，这些信号级联负责调节细胞增殖、细胞死亡和细胞分化。环境因素，如饮食成分，以及肿瘤抑制基因或癌基因的基因突变，都是已知的介导肠道癌症的发生和发展的因素。最近的证据表明，APC(结肠腺瘤性息肉病)和RAS信号通路在这些过程中至关重要，它们在绝大多数结肠癌细胞中被发现调控不当(Pennisi，1998，McCormick，1999)。小鼠模型提供了极好的机会来识别和定义与结直肠癌相关的基因的作用。该项目的目的是通过组织特异性表达转基因(如APC靶基因K-RAS)和利用D.Louvard组中现有的转基因动物组合几个位点上的突变等位基因来建立结肠癌发生的小鼠模型。由此产生的转基因动物将被用分子、生化和免疫组织化学技术进行分析，以阐明所选转基因对细胞数量稳态和致癌的重要性。

Cancers of the intestine are among the most frequent tumors in the western countries. The process of colon carcinogenesis involves the stepwise, progressive disruption of cellular signalling cascades which are responsible for regulating cell proliferation, cell death and cellular differentiation. Environmental factors, like dietary components, as well as genetic mutations in tumor suppressor genes or oncogenes are known to mediate the initiation and progression of cancers in the intestinal tract. Recent evidence demonstrates the pivotal importance of the APC (adenomatous polyposis coli) and Ras signalling pathways in these processes, which are found to be misregulated in the vast majority of colon cancer cells (Pennisi, 1998, McCormick,1999). Murine models provide excellent opportunities to identify and define the roles of genes involved in colorectal cancer. The aim of this project is the establishment of mouse models for colon carcinogenesis by tissue-specific expression of transgenes like K-Ras an the APC target ß-catenin, and combination of mutated alleles in several loci by taking use of the already existing transgenic animals that are available in the group of D. Louvard. The resulting transgenic animals will be analyzed with molecular, biochemical and immunohistochemical techniques in order to elucidate the importance of the chosen transgenes for cell number homeostasis and carcinogenesis.