Colorectal cancer is one of the leading cancers in Puerto Rican, second only to prostate and breast cancer. Inflammatory bowel diseases such as ulcerative colitis and Crohn's disease have been linked to the development of colorectal cancer. Evidence obtained by us and others have suggested that substance P (SP) and its high affinity receptor neurokinin-1 receptor (NK-1R, tachykinin receptor 1) play a pivotal role in inflammatory bowel diseases. Both NK-1R and cyclooxygenase-2 (Cox-2) are upregulated in patients with inflammatory bowel diseases. However, the roles of NK-1R-mediated signaling pathways in the pathogenesis of precancerous and cancerous lesions in ulcerative-associated colorectal cancer are not known. The long-term goals of this research project are to understand molecular mechanisms of ulcerative colitis-associated colorectal cancer and to target key signaling molecules in the development of ulcerative colitis-associated colorectal cancer for preventive and therapeutic intervention. The current study is designed to test the central hypothesis that NK-1R plays a key role in up regulation of Cox-2 in our rat model of colitis-associated dysplasia, and that the epidermal growth factor receptor (EGFR) and Src family tyrosine kinases (SFKs) are involved in NK-1R signaling in colon carcinoma cells, and in the development of precancerous lesions in this model of colitis-associated dysplasia.
Three specific aims will be pursued in this collaborative research project that combines the strength of Dr. Appleyard in the rat model of ulcerative colitis-associated colorectal cancer and the expertise of Dr. Wu in growth factor receptor and G protein-coupled receptor (GPCR) signaling. In addition to giving novel insights into the roles of NK-1R and its mediators in the development of colorectal cancer, this collaborative research project will provide Dr. Appleyard with an excellent platform to strengthen her competitiveness in the areas of biochemical and molecular cancer research. This in turn will increase the likelihood for Dr. Appleyard in the Minority-Serving Institute (MSI) to successfully compete for a R01 grant from the National Cancer Institute (NCI) and will increase the quality of graduate education at the MSI. ? ? ?
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