Targeting SP-NK1R-EGFR interactions in colitis associated dysplasia.
Neurokinin-1 Receptor and Its Signaling Components in Colitis-associated Dysplasia
Jie Wu, Ph.D., Associate Professor, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
Caroline B. Appleyard, Ph.D., Associate Professor, Ponce School of Medicine, Puerto Rico
Colorectal cancer is one of the leading cancers in Puerto Ricans. Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease have been linked to the development of colorectal cancer. The neurokinin-1 receptor (NK-1R, tachykinin receptor 1) 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 upregulation 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:
Specific Aim I: To investigate the role of NK-1R and EGFR in colitis-associated dysplasia.
Specific Aim II: To analyze the roles of EGFR and SFKs in NK-1R-mediated cell signaling and proliferation in colorectal carcinoma cells.
Specific Aim III: To evaluate the efficacies of EGFR, SFK, and COX-2 inhibitors on inhibition of the development of UC-associated dysplasia in a rat model.
This collaborative research project 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 signaling. In addition to giving novel insights into the mechanisms of colorectal cancer development, this project will provide Dr. Appleyard with a platform to strengthen her competitiveness in molecular cancer research and will increase the quality of graduate education at the Minority Serving Institute.