Further Genetic Analysis of PPARg in Min Tumorigenesis

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DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the major malignancies in the United States, accounting for 130,000 new cases and more than 50,000 deaths each year. Notably, the incidence and mortality rates from CRC have remained fairly constant over the past three decades despite advances in early detection and therapy. To develop effective prevention and therapeutic modalities for CRC an emergent challenge for cancer investigators is to identify and characterize the constellation of genetic factors that underlie CRC susceptibility. Key research tools are genetically defined mouse models such as the ApcMin/+ mouse. We have previously used the sensitized Min mouse to map and functionally clone a major modifier of Min-induced tumorigenesis, the secretory phospholipase Pla2g2a. This proposal extends our previous work by using the Min mouse to examine the phenotype of a conditional knockout of the nuclear receptor PPARg. Intercrosses between mice carrying floxxed alleles of PPARg, mice expressing the Cre recombinase driven by the intestine-specific villin promoter, and Min mice will provide Min test mice completely deficient for PPARg in the intestine. This experiment will unequivocally address the role of PPARg in Apc-mediated mouse colon tumorigenesis. Introduction of a wildtype Pla2g2a transgene into this test cross will examine potential genetic interactions between Pla2g2a and PPARg.