REGULATION OF HUMAN PAPILLOMAVIRUSES IN ORAL MUCOSA

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The candidate, Dr. Zhuo Chen, is currently a full-time research assistant professor in the Department of Basic Sciences at the University of Texas Dental Branch, which is located in the Texas Medical Center which ius the largest medical care and research complex in the world. Dr. Chen acquired excellent comprehensive training in biochemistry and molecular biology from her Ph.D and postdoctoral programs at Louisiana State University before joining the faculty, so that she is able to rapidly develop independent research programs using molecular techniques to study diseases in oral cavity. In 1996, she received an R29 (FIRST) Award from the National Cancer Institute to study the regulation of human papillomaviruses (HPV) in oral mucosa with an emphasis on regulatory mechanisms which function in tumor cells to allow the over-expression of the transforming genes of HPV. A K02 Award would provide the "chain" to help her to continue connecting her background and training in molecular biology and biochemistry to dental research, specifically to oral cancer. She would benefit by having additional resources and time to build a more comprehensive research program in oral carcinogenesis by combining the findings from this research with those of her other ongoing projects dealing with over-expression of oncogenes in oral cancer. This expanded focus will facilitate and lead to development of a proposal for funding via the RO1 mechanism. Her ultimate goal is to provide the basis for a better understanding of gene expression in oral epithelial cells and oral cancer cells. The proposed K02 project is based on, as well as an extension of, her R29 to further investigate why oral epithelial cells provide the unique environment for HPV-induced transformation. As the first part of this study, she has detected functionally significant mutations in the HPV long control region (LCR) isolated from oral cancer cells. The hypothesis is that cellular proteins or their complexes are able to act on the mutated LCR in a specific manner to activate the transcription of the E6 and E7 oncogenes, leading to malignant transformation of epithelial cells. This work will (i) identify and characterize the major cellular protein factors and complexes that trans- regulate E6 and E7 genes from HPV-16 and -18 in both normal and malignant oral epithelial cells; (ii) determine cell-type specific interactions between the HPV LCR and major regulatory protein factors which are responsible for activation of E6 and E7 gene expression in malignant oral epithelial cells; (iii) delineate the interactions between these major factors and the LCR of HPV-16 and-18 in both normal and malignant oral epithelial cells. This project will increase our understanding of HPV gene regulation in normal and malignant oral epithelial cells. In addition, identification of cis-elements and major cellular proteins involved in HPV-related oral cancers will provide a fundamental basis by which to develop potential gene therapy strategies against cancer in the oral cavity.