The intestinal epithelium is self-renewing. This tissue is mitotically very active with approximately 1011 cell divisions per day. Surprisingly, the incidence rate of colorectal cancer only rises sharply after the sixth decade of life, indicating that homeostasis must be maintained by numerous layers of regulation. This regulation is breached in individuals afflicted with an autosomal dominant cancer syndrome called familial adenomatous polyposis (FAP). This syndrome is characterized by the formation of numerous colonic adenomas that can progress to adenocarcinomas. Primary treatment is resection or removal of the colon, followed by radiation and/or chemotherapy. The molecular basis of FAP is beginning to be understood. It arises from mutations in the adenomatous polyposis coli gene. The laboratory of Dr. W. F. Dove identified a mutation in the mouse homolog of adenomatous polyposis coli gene, ApcMin. Mice carrying a single copy of this mutation develop multiple adenomas throughout the intestinal tract. The goal of the proposed study is to identify modifiers of this phenotype. One approach is based on testing candidate genes that have been implicated in human colorectal cancer. If alleles of these genes affect the Min phenotype, then the combination of these alleles and Min is a better model of the human disease and should facilitate the development of gene and drug therapies. The other approaches are designed to identify novel modifiers of the Min phenotype either by mapping a polymorphic modifier isolated by crossing inbred strains or by mapping mutant modifiers isolated in a genetic screen. Such modifiers may provide new insights into the network of genes that can impact intestinal neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA077946-01
Application #
2642965
Study Section
Special Emphasis Panel (ZRG2-SSS-1 (01))
Program Officer
Lohrey, Nancy
Project Start
1998-12-21
Project End
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
1
Fiscal Year
1998
Total Cost
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