They have developed evidence that TGF-b inhibition of normal intestinal epithelial cell proliferation through the down regulation of an important proto-oncogene, cyclin D1. The central hypotheses for this project are 1) that the TGF-b ligands and their signaling receptors function as important normal constraints on intestinal growth; 2) loss of TGF-b tumor suppressor function is an important early step in the development of dysplastic lesions and cancers of the intestine, and 3) over expression of cyclin D1 may be a mechanism by which tumor cells escape the growth-inhibitory actions of TGF-b. The long term goal of this project is to develop novel targets for therapeutic intervention within these pathways that will beneficial in the treatment and/or prevention of colorectal cancer. This application will be focused on testing the hypotheses through the following specific aims:
Aim 1) To determine the role of the TGF-b Type II Receptor (TbIIR) in rodent models of intestinal hyperplasia and neoplasia. a) The expression of TbIIR and its association with cyclin D1 and K-ras mutation will be examined in Multiple Intestinal Neoplasia (Min) mice and in colonic lesions in azoxymethane treated mice and rats. b) Intestinal carcinogenesis will be examined in mice that express a cominate negative form of the TbIIR in the intestine. C) Crossbreeding of Min mice with transgenic mice that express the dominant negative mutant TbIIR.
Aim 2) To determine whether over expression of cyclin D1 in the mouse intestine results in hyperplasia and neoplasia.
Aim 3) Examine freshly-obtained surgical specimens to determine whether the abnormalities in TbIIR and down stream effectors observed in experimental rodent models are found in human colorectal polyps and cancers. Human colorectal polyps and cancers will be examined to determine whether there is a correlation between cyclin D1 expression, K-ras mutation, and down regulation of the TbIIR. These studies will provide validation for the rodent and cell culture experimental models that will be used to test novel therapeutic interventions aimed at correcting the lesions detected by this project.
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