END mutagenesis of the rat germline followed by screening for nonsense alleles in the Adenomatous polyposis coli (Ape) gene has generated inbred Fischer344 kindred carrying an X pcam1137 nonsense allele. Heterozygotes for this mutation develop multiple colonic polyps within 3 months of age; the ratio of colonic polyps to neoplasms in the small intestine is far higher than that observed in mouse models of human colorectal cancer. For this reason, the kindred is designated F344-Pirc (polyposis in the rat colon). Research is proposed to address the following issues: To investigate the importance of conservative somatic recombination in the initiation of the familial adenoma and microadenoma To identify dominant resistance and susceptibility genetic modifiers of the Pirc phenotype in the rat genome To investigate invasive and metastatic stages of colon cancer that may be permitted by the longevity we observe in the initial cohort of Pirc rats To develop imaging of the Pirc rat in vivo by microCT, microPET and endoscopy, establishing the potential to perform longitudinal studies of chemopreventive and therapeutic treatment, using celecoxib and 5-FU as test cases ? ? ? ?
