Previous studies of the investigator identified a novel tyrosine kinase, Sik, expressed in intestinal epithelial cells undergoing terminal differentiation in the small and large intestines of mice. The investigator also showed that the human homologue of this kinase is a known protein previously identified in a metastatic breast tumor (Brk). Based on these studies, the goal of the current project is to identify the biological functions of Sik/Brk, and also to determine whether Brk expression is altered during the progression of colon cancer.
Four specific aims are proposed. In the first, expression and/or activation of Brk in sections of human colon adenomas and carcinomas will be compared to normal tissues. In the second, cell line models will be transfected with various Sik constructs and effects on proliferation or differentiation examined. In the third aim, transgenic approaches will be used to ablate Sik function in the mouse intestine, using a dominant negative mutant targeted using the iFABP promoter. Finally, the applicant will examine the effect of knocking out Sik expression in mice. Overall, the studies are hoped to clarify the biological role of the novel epithelial cell specific tyrosine kinase, Sik/Brk, in normal intestinal epithelial cells as well as in the progression of intestinal malignancies.
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