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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA125591-03S1
Application #
7848038
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mietz, Judy
Project Start
2009-06-01
Project End
2010-09-30
Budget Start
2009-06-01
Budget End
2010-09-30
Support Year
3
Fiscal Year
2009
Total Cost
$31,025
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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; 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
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
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