REGULATION OF HUMAN PAPILLOMAVIRUSES IN ORAL MUCOSA

候选人卓晨博士目前是一名全职研究助理 德克萨斯大学基础科学系教授 牙科分支，这是位于得克萨斯州医疗中心，其中使用 世界上最大的医疗保健和研究综合体。陈博士获得 在生物化学和分子生物学方面的优秀综合培训 从她在路易斯安那州立大学的博士和博士后项目 在加入教师之前，她能够迅速发展， 利用分子技术研究疾病的独立研究项目 在口腔中。1996年，她获得了R29（FIRST）奖。 美国国家癌症研究所研究人类 口腔粘膜中的乳头状瘤病毒（HPV），重点是调节 在肿瘤细胞中起作用的机制， HPV的转化基因K 02奖将提供“链条”， 帮助她继续将她的背景和分子训练联系起来， 生物学和生物化学到牙科研究，特别是口腔癌。 她将受益于有额外的资源和时间来建立一个更 口腔癌发生的综合研究计划， 这项研究的结果与她其他正在进行的项目的结果 研究口腔癌中癌基因的过度表达。这一扩大 重点将促进并导致拟订一项筹资提案 通过RO 1机制。她的最终目标是为一个 更好地了解口腔上皮细胞和口腔粘膜中的基因表达 癌细胞拟议的K 02项目是基于，以及 延伸，她的R29，以进一步研究为什么口腔上皮细胞 为HPV诱导的转化提供独特的环境。为 在这项研究的第一部分，她发现了功能显著的 从口腔癌中分离的HPV长控制区（LCR）突变 细胞假设是细胞蛋白质或其复合物 能够以特异性方式作用于突变的LCR以激活 E6和E7癌基因的转录，导致恶性肿瘤。 上皮细胞的转化。这项工作将（一）确定和 表征主要的细胞蛋白质因子和复合物，反式- 在正常和恶性肿瘤中调节来自HPV-16和-18的E6和E7基因 口腔上皮细胞;（ii）确定细胞类型特异性相互作用 HPV LCR和主要调节蛋白因子之间的关系， E6和E7基因在口腔癌组织中的表达 上皮细胞;（iii）描绘这些主要的细胞之间的相互作用， HPV-16和HPV-18在正常口腔粘膜和口腔癌组织中的LCR 上皮细胞本项目将增加我们对HPV基因的了解 正常和恶性口腔上皮细胞中的调节。此外，本发明还提供了一种方法， 参与的顺式元件和主要细胞蛋白的鉴定 HPV相关的口腔癌将提供一个基本的基础， 开发针对口腔癌的潜在基因治疗策略 腔

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.