Colon-specific Transgenic Mouse for Cancer Research

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DESCRIPTION (provided by applicant): A barrier to understanding the molecular etiology of colon cancer is the lack of well-characterized animal models that recapitulate the etiology of human sporadic colon cancer. While we have learned a great deal from cancers resulting from various chemically induced- or genetically programmed-rodent models, the cancers that develop in these models are often significantly different from human colon cancer in terms of latency, intestinal location, or molecular signature. Mechanistic and prevention focused colon cancer research requires the development of animal models that permit precisely timed, colon-specific modification of intestinal biology. The goal of our proposal is to address an area of special interest listed in PA-06-149: "Development, characterization and utilization of novel cellular and animal models of gastrointestinal diseases, including associated cancers." To meet this challenge we have developed two specific aims for the proposed research. First, we will use the promoter that drives colon-specific expression of the carbonic anhydrase 1 (CA1) gene to create a transgenic mouse with colon-epithelial cell-specific expression of Cre recombinase. This model will be useful for making colon specific gene knockout mice. Characterization of Cre transgene expression will be assessed by PCR analysis, immunohistochemistry, and by crossing our transgenic mice to the ROSA26R indicator mouse. Second, we will cross our CA1-Cre transgenic mice to mice with a floxed APC allele to create mice with colon-specific deletion of this critical oncogene; APC inactivating mutations are an early molecular event in the development of sporadic cancer of the distal colon. The development of colon cancer in the double transgenic mice will be assessed under basal conditions and after promotion with an inflammatory agent. The colon-specific APC null mouse will be an improved model of sporadic colon cancer. More importantly, it will confirm the utility and flexibility of our new CA1-Cre model for making future colon-specific knockout and transgenic mice. This work is critical to public health because it will serve as a foundation for making better animal models to study the mechanism of colon cancer. In addition, colon cancer models made with the new transgenic mouse will be useful for testing agents for their ability to treat and prevent cancer.