THE ROLE OF EPSTEIN-BARR VIRUS EBNA1, LMP1 AND LMP2A PRO

eb病毒（EBV）在青少年中引起传染性单核细胞增多症，在艾滋病患者和器官移植免疫抑制患者中引起恶性B淋巴细胞增殖。EBV在病因学上与非洲伯基特淋巴瘤和鼻咽癌有关。在体外，EBV转化、潜伏感染的B淋巴细胞含有EBV发作体和9种病毒编码蛋白。其中6个是核蛋白（ebna）， 3个是整体膜蛋白LMP1、LMP2A和LMP2B。这9种蛋白被认为介导潜伏病毒感染或b淋巴细胞增殖，因此正在深入研究中。除了EBNA1维持发作所需的潜伏表达蛋白外，LMP1和LMP2A是EBV相关恶性肿瘤中一致检测到的潜伏表达蛋白，并且EBNA1和LMP2A是潜伏EBV感染个体B淋巴细胞PCR分析中检测到的唯一EBV特异性信息。鼻咽癌（NPC）发生在世界各地，但其发病率具有显著的地理和人群差异。虽然鼻咽癌在欧洲和北美高加索人中很少见，但在中国南部和东南亚的发病率很高，可能占所有癌症的25%。在其他中国人群、阿拉斯加爱斯基摩人和地中海非洲人中也有较高的发病率。鼻咽癌分为三种类型：鳞状细胞癌（SCC）、非角化癌（NKC）和未分化癌（UC）。最近的报告表明，所有形式的鼻咽癌均被EBV基因组克隆群体感染。在所有形式的鼻咽癌中，都表达相同的EBV基因，即LMP1、LMP2A和EBNA1。本研究计划分析EBNA1、LMP1和LMP2A在鼻咽癌发病机制中的作用，并可能为其他ebv相关的恶性肿瘤提供信息。在这四个具体目标中，我们建议分析表达EBNA1、LMP1和LMP2A的角质形成细胞的体外表型，并建立转基因模型系统来研究LMP2A在NPC中的作用以及与LMP1可能的合作。了解EBNA1、LMP1和LMP2A在鼻咽癌中的作用可能会为鼻咽癌的治疗提供新的治疗方法，并更好地了解影响口腔癌发展的因素。

Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant B lymphocyte proliferation in AIDS patients and patients undergoing immune suppression for organ transplantation. EBV is etiologically associated with African Burkitt's lymphoma and nasopharyngeal carcinoma. In vitro, EBV transformed, latently infected B lymphocytes contain EBV epsisomes and nine virus encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. These nine proteins are presumed to mediate latent virus infection or B. lymphocyte proliferation and thus are under intense investigation. Besides EBNA1, which is required for episome maintenance, LMP1 and LMP2A are the latently expressed proteins consistently detected in EBV related malignancies, and the EBNA1 and LMP2A messages are the only EBV- specific messages detected in PCR analysis of B lymphocytes from individuals harboring latent EBV infections. Nasopharyngeal carcinoma (NPC) occurs worldwide but is characterized by marked geographical and population differences in incidence. While rare among Europeans and North American Caucasians, NPC develops with high incidence in southern China and southeast Asia where it may represent 25 percent of all cancers. The tumor also occurs with increased incidence in other Chinese populations, Alaskan Eskimos, and Mediterranean Africans. NPC has been classified into three types: squamous cell carcinoma (SCC), nonkeratinizing carcinoma (NKC), and undifferentiated carcinoma (UC). Recent reports indicate that all forms of NPC are uniformly infected with clonal populations of EBV genomes. In all forms of NPC, the same set of EBV genes are expressed namely LMP1, LMP2A, and EBNA1. This research grant proposes to analyze the role of EBNA1, LMP1, and LMP2A in the pathogenesis of NPC and may prove informative for other EBV-associated malignancies. In the four Specific Aims, we propose to analyze the in vitro phenotype of keratinocytes expressing EBNA1, LMP1, and LMP2A and to develop a transgenic model system to investigate the role of LMP2A in NPC and the possible cooperation with LMP1. Understanding the role of EBNA1, LMP1, and, LMP2A in NPC may suggest novel therapeutics for the treatment of NPC, and a better understanding of factors that can influence the development of oral cancers.