Colorectal cancer is the second leading cause of cancer death in the United States, accounting for 150,000 new cases and 56,000 deaths annually. The events leading to the pathogenesis of colorectal cancer are thought to be initiated by genetic mutations or alterations in key tumor-suppressor genes and cell-signaling pathways, such as p53 and the APC/beta-catenin/Wnt pathway. Less is known about the mechanisms by which environmental factors, such as diet and infectious agents, contribute to the pathogenesis of colon cancer. One such infectious agent, the human JC polyomavirus (JCV), has recently been found in up to 80% of human colon cancers. The association of JCV with cancer is thought to be due to the expression of the early viral gene product, T-antigen, based on evidence from animal models and, more recently, in human tumors. This oncoprotein has multiple functions, including helicase and DNA-binding activities, as well as disrupting cell cycle control and apoptosis by binding the tumor suppressor genes pRb and p53, respectively. The mechanism by which JCV contributes to the pathogenesis of human colorectal cancer is unknown, though preliminary evidence from other laboratories suggests that alterations within the viral transcription control region may stimulate viral gene expression. This research proposal seeks to determine the sequence elements within the control region and identify cell-specific transcription factors that stimulate viral gene expression in colon cancer cells. Interactions between T-antigen and important cell-signaling pathways will also be investigated, with particular attention to the interaction between T-antigen and p53, as well as the (-catenin/Wnt pathway. Finally, animal models for JCV-induced colon cancers will be developed by targeting JC virus T-antigen expression to the gastrointestinal tract using liposome-mediated gene delivery as well as a transgenic mouse approach. Dr. Hiroomi Tada, the Principal Investigator of this grant application, has broad exposure to both basic science research and clinical medicine. This was accomplished during training in an M.D.-Ph.D. program, as a surgical resident and research fellow, and as a clinical fellow in surgical oncology at M.D. Anderson Cancer Center. As a new Assistant Professor of Surgery, the PI's long-term goals are to establish a laboratory-based research program that complements a strong clinical interest in the pathogenesis and treatment of gastrointestinal malignancies. The applicant has a strong background in virology and molecular biology with the clinical experience of treating and caring for patients at various stages of disease. With an additional mentored research experience and didactic work, Dr. Tada will be able to contribute significantly to an understanding of the mechanisms involved in the pathogenesis of colon cancer, and be in an excellent position to compete for funding as an independent investigator in the future.
