Our Center has been involved in developing and analyzing a large number of genetically modified mouse models for colon cancer. Study of these models provided valuable information about the initiation and progression of colorectal cancer and the roles of many different genes in that process. More recently we have developed floxed alleles of three genes;Ape, Mlh1 and Msh2. When adeno-cre is introduced into the rectum of the floxed allele of Ape, the mice develop one tumor at the site of injection. We have developed a novel colonoscope for mice that allows us to examine the onset and progression of the tumors without sacrificing the mice. We now propose a series of experiments to establish the different mouse models that we have already developed for translational research. We have used our mouse models to identify protein based biomarkers that enable us to distinguish between normal and tumor bearing mice at an early stage. In a parallel effort we have collaborated with the Women's Health Initiative and the NCI's early detection research network (EDRN) to identify a similar set of protein markers based on examination of plasma samples from women prior to diagnosis with colon cancer. There is a significant overlap between the proteins identified from the mouse model and the human samples. We will use mouse models to bring these markers into the clinical setting. The Apc-Adeno-cre model described above is an excellent model for human sporadic colorectal cancer. We will use our models to evaluate a large number of drugs that might be effective in colon cancer. All of these studies are going to be facilitated by the use of novel imaging methodologies that allow us to follow the progression of tumors in individual mice in a non-invasive fashion. Germline mutations in human mismatch repair genes MLH1 and MSH2 result in a cancer predisposition syndrome, termed hereditary non-polyposis colorectal cancer (HNPCC). Mismatch repair (MMR) deficiency is also observed in a large number of sporadic tumors in different tissues. Understanding how tumors with MMR deficiency respond to chemotherapeutic regimens and other drugs is critical in developing new therapeutic approaches. We propose such experiments. Mismatch repair genes function within large DNA binding complexes. All of the critical members of these complexes have not been identified. Using novel models and mass spectrometry we propose to identify all of the members of the complex. These efforts will significantly advance the use of mouse models for human cancer translational efforts.
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