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 ? ? ? ?
|Irving, Amy A; Plum, Lori A; Blaser, William J et al. (2015) Cholecalciferol or 25-hydroxycholecalciferol neither prevents nor treats adenomas in a rat model of familial colon cancer. J Nutr 145:291-8|
|Irving, Amy A; Young, Lindsay B; Pleiman, Jennifer K et al. (2014) A simple, quantitative method using alginate gel to determine rat colonic tumor volume in vivo. Comp Med 64:128-34|
|Irving, Amy A; Yoshimi, Kazuto; Hart, Marcia L et al. (2014) The utility of Apc-mutant rats in modeling human colon cancer. Dis Model Mech 7:1215-25|
|Amos-Landgraf, James M; Heijmans, Jarom; Wielenga, Mattheus C B et al. (2014) Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones. Proc Natl Acad Sci U S A 111:16514-9|
|Amos-Landgraf, James M; Irving, Amy A; Hartman, Cory et al. (2012) Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms. Proc Natl Acad Sci U S A 109:2060-5|
|Irving, Amy A; Halberg, Richard B; Albrecht, Dawn M et al. (2011) Supplementation by vitamin D compounds does not affect colonic tumor development in vitamin D sufficient murine models. Arch Biochem Biophys 515:64-71|