This proposal outlines a four-year plan utilizing a genetic approach to search for second site tumor modifiers of retinoblastoma (Rb) in the mouse. Strategies will search for both dominant and recessive tumor modifiers. A random germline approach using ethylnitrosourea (ENU) mutagenesis will be employed to search for such mutations. Such methods have been used to isolate the Min (multiple intestinal neoplasia) allele of adenomatous polyposis coli, new PKU mutations as well as defining the Clock mutation in the mouse. Genetic crosses will be done in a way to facilitate mapping of newly acquired mutations that result in retinal tumors. The first and part of the second year will be focused on the mapping of a known modifier locus which affects the number of intestinal tumors in the Min mouse. During this time, mouse strains will be bred to enable the generation of Rb mouse models and identification of second-site Rb- modifiers. The third and fourth years will be devoted to exploring screens for Rb dominant and recessive tumor enhancers using ENU germline mutagenesis. This genetic system has profound potential in not only isolating such tumor enhancers, but also in identifying molecules affecting progression of retinoblastoma. The use of the laboratory mouse would allow methods of somatic and germline mutagenesis, targeted mutagenesis, positional cloning and chimerism to explore a wide spectrum of ocular malignancy and disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA084146-02
Application #
6377659
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2000-09-08
Project End
2004-08-31
Budget Start
2001-09-26
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$139,725
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
Zahm, Christopher D; Szulczewski, Joseph M; Leystra, Alyssa A et al. (2016) Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture. PLoS One 11:e0150170
Thliveris, Andrew T; Schwefel, Brittany; Clipson, Linda et al. (2013) Transformation of epithelial cells through recruitment leads to polyclonal intestinal tumors. Proc Natl Acad Sci U S A 110:11523-8
Thliveris, Andrew T; Halberg, Richard B; Clipson, Linda et al. (2005) Polyclonality of familial murine adenomas: analyses of mouse chimeras with low tumor multiplicity suggest short-range interactions. Proc Natl Acad Sci U S A 102:6960-5