Establishment and Characterisation of Mouse Models for Colorectal Carcinoma

肠癌是西方国家最常见的肿瘤之一。结肠癌发生的过程涉及负责调节细胞增殖、细胞死亡和细胞分化的细胞信号级联的逐步、进行性破坏。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已知介导肠道癌症的发生和发展。最近的证据表明APC（腺瘤性结肠息肉病）和Ras信号传导途径在这些过程中的关键重要性，发现它们在绝大多数结肠癌细胞中被错误调节（Pennisi，1998，McCormick，1999）。小鼠模型提供了极好的机会，以确定和定义的基因参与结直肠癌的作用。该项目的目的是通过组织特异性表达转基因如K-Ras和APC靶点β-连环蛋白，并通过利用D组中已有的转基因动物在几个位点中组合突变等位基因，建立结肠癌发生的小鼠模型。卢瓦德将用分子、生物化学和免疫组织化学技术分析所得转基因动物，以阐明所选转基因对细胞数量稳态和致癌作用的重要性。

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.