We are requesting support to continue our membership in the MMHCC. During the current grant period, we have generated and analyzed several mouse models for human FAP and HNPCC. We have also modeled loss of heterozygosity in mice and a point mutation of MSH6 that provided new insights into GI tumorigenesis. The active investigators of our program are Kucherlapati, Edelmann and Lipkin. In this application Dr. Rakesh Jain of MGH, an expert in intravital imaging will join our group. Patients with germline mutations in APC develop FAP and Gardner syndrome and those with germline mutations in MLH1 and MSH2 develop HNPCC. Both of these disorders are characterized by tumors in the GI tract and other locations in the body. These results suggest that mutations in these genes are initiating events in a number of different tumor types. We propose to use the cre-loxP system to make conditional knockout mice to generate mouse models for tumors in the skin, breast and other tissues. These mice will also be used to model sporadic colorectal tumorigenesis by inactivating the gene in somatic colorectal mucosa. This will be accomplished by introducing Adeno-cre by enema. Adeno-cre will also be used to generate sporadic mouse models for skin and lung cancer. To follow the cells that have undergone the targeted gene inactivation, we propose to develop a novel system, in which gene inactivation results in the simultaneous activation of a cellular marker such as beta-galactosidase or green fluorescent protein (GFP). The natural history of the tumors will be examined by conventional methods as well as by intravital microscopy. We propose to construct a multiphoton laser scanning micro-endoscope that can be used image colorectal tumor progression in mice with a very high resolution. Intravital imaging will also be used to examine angiogenesis in our tumor models. We propose a novel approach to examine gene-environment interactions. For example to study the role of obesity we will combine Apc or Msh2 mutant mice with ob/ob mice that normally become obese. We also propose to examine the very early and very late stages of tumor formation by using the cellular tagging approach mentioned above. All of these studies will be augmented by genomic approaches that facilitate discovery of new genes and pathways that are critical for the development of tumors in the Apc, Mlhl and Msh2 mutant mice.
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