International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 31 - A SENSITIZED ENU MUTAGENESIS SCREEN IN ANIMAL MODELS OF CHRONIC INFLAMMATORY DISEASES AS A TOOL FOR DRUG TARGET DISCOVERY

Douni E
Biomedical Sciences Research Center “Alexander Fleming”

Co-Authors: Sekara E, Kamber M, Mantellou M, Kontoyiannis D, Kollias G
Institutions: Biomedical Sciences Research Center “Alexander Fleming”

Random mutagenesis on a genome-wide scale, is an attractive method to sample, without bias, the role of virtually all genes in a particular pathological process. Mutant mice carrying a deletion of the 3' AU-rich elements (ARE) from the TNF mRNA, over-express TNF and develop chronic inflammatory poly-arthritis and Crohn's-like inflammatory bowel disease (IBD) with 100% incidence at 3 months of age. We have been using these TNFΔARE mutant mice, in a sensitized ENU mutagenesis screen, to identify novel genes that modify the disease phenotype. We have optimized chemical mutagenesis in the TNFΔARE mice by careful titration of various ENU doses in their original mixed C57BL/6 x 129SvEv genetic background. By using simple and accurate phenotypic screens, clinical score for arthritis and macroscopic or histological analysis for IBD, we are selecting the individual progeny that no longer suffer from the disease. In this approach large numbers of targets can be validated concurrently in individual mice using disease-specific dominant or recessive screens. So far, with this approach we have screened 90 G3 pedigrees, 3 of which show a dramatic delay on arthritis onset and progression. In consequent genome analyses, it will be possible to define the specific mutated genes, which are responsible for the therapeutic effects in the disease models, and to assign effective drug targets for these important diseases.


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