Inducible colon-specific transgenic mouse for cancer research

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DESCRIPTION (provided by applicant): Over the past 20 years our understanding of the molecular etiology of colon cancer has expanded dramatically. Despite this, colon cancer remains a significant health problem in the US. One of the barriers to progress in the field is the lack of well-characterized animal models that recapitulate the etiology of human colon cancer. While we have learned a great deal from cancers resulting from various chemically induced- or genetically programmed-rodent models, the cancer that develops in these models is 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. Our goal for the proposed research is to use the promoter that drives large intestine-specific expression of the carbonic anhydrase 1 (CA1) gene to create a transgenic mouse with colon-epithelial cell-specific expression of Cre recombinase (Cre)-fused to a modified estrogen receptor (ER) ligand binding domain with high affinity only for the estrogen analog tamoxifen (CAC- ERT2). The ERT2 portion of the fusion gene confers taxomifen-inducibility to the transgene and permits temporally controlled deletion of floxed alleles in the mouse genome. A transgene vector has been produced and it will be used to produce mice at the Purdue Transgenic Mouse Core Facility. Transgene expression level and tissue distribution will be assessed by PCR. Inducibility of transgene function by tamoxifen will be assessed after crossing the CAC-ERT2 mouse to the ROSA26R indicator mouse. The ability of tamoxifen to induce tumor formation will be assessed in CAC-ERT2 mice crossed to mice with one or two floxed APC alleles. Additional studies will be done in the presence of colonic inflammation induced by dextran sulfate sodium (DSS). Upon completion of the project, the CAC-ERT2 mouse will be the only transgenic model that both limits Cre expression to the epithelial cells of the large intestine and permits control over when Cre functions to delete floxed alleles. This will permit colon cancer researchers to easily combine genetic mutations (i.e. with multiple floxed alleles relevant to colon cancer etiology) and initiate colon cancer at any stage of life. This will permit more careful assessment of mechanisms of carcinogenesis and improved testing of chemopreventative or therapeutic agents in adult mice. While our interests are in using this model for colon cancer, this model will also be useful for researchers interested in inflammatory conditions of the lower bowel (i.e. IBD, Crohn's disease). 1 PUBLIC HEALTH RELEVANCE: Colon cancer is a common form of cancer in the US and scientists. Research to develop effective treatment and prevention strategies is hampered by the lack of animal models that reproduce the features of human sporadic colon cancer. Our proposed research will create a new genetically modified mouse model that overcomes the limitations of existing animal models for colon cancer research.