PI: Vladimír Kořínek Genetically Modified Mice as a Tool to Study Renewal and Neoplastic Transformation of Gastrointestinal Epithelia

The single-layer epithelia of the small intestine and colon represent the most rapidly self-renewing adult tissue that completely regenerates approximately every five days. The proper maintenance of epithelial architecture is controlled by various signaling pathways that regulate the balance between the opposing processes of proliferation and differentiation. These pathways include Wnt/β-catenin, Hedgehog and Notch signaling, the ephrin type-B receptor (EphB)/ephrin-B cell communication system, the bone morphogenetic protein (BMP) signal transduction pathway and signaling downstream of the epidermal growth factor receptor (EGFR). Importantly, the majority of these pathways is deregulated in carcinoma of colon and rectum (colorectal cancer).

Colorectal cancer represents the third most common human malignancy worldwide. It is estimated that more than one million patients are clinically diagnosed each year; up to one third of the cases constitute metastatic settings resulting in a disease-related mortality rate exceeding 30%.

Colorectal cancers are characterized by a complex genomic “landscape”; individual tumors harbor nine rearranged loci on average and a median of 76 non-silent mutations. However, only a fraction of these changes is considered to be causative in tumor initiation and progression. The project will be focused on the on the analysis of crucial molecular mechanisms involved in physiological renewal and neoplastic transformation of cells of the gastrointestinal tract. The gene manipulation in mouse will be used as the main toll to accomplish the aims of the project.

The aims of the project are: (1) generation of novel transgenic mouse strains expressing DNA recombinases in cells of the gastrointestinal tissues; (2) identification and characterization of genes that encode tumor suppressors or oncogenes responsible for initiation or progression of gastrointestinal neoplasia; (3) generation and analysis of mice harboring conditional alleles of the selected gene(s); (4) alternatively, generation and analysis of mice harboring an activated oncogene in selected tissues.