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

Epstein-Barr 病毒 EBNA1、LMP1 和 LMP2A PRO 的作用

• 批准号: 6611460
• 负责人: Richard M Longnecker
• 金额: $ 27.51万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611460
• 关键词: Epstein Barr virus; carcinoma; gene expression; genetically modified animals; keratinocyte; laboratory mouse; nasopharyngeal neoplasms; phenotype; viral carcinogenesis; virus protein; virus related neoplasm /cancer

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.

EB病毒（EBV）引起青少年的传染性单核细胞增多症和艾滋病患者和接受器官移植的免疫抑制的患者的恶性B淋巴细胞增殖。 EBV与非洲伯基特淋巴瘤和鼻咽癌的病因有关。 在体外，EBV转化的潜伏感染的B淋巴细胞含有EBV epsisomes和九种病毒编码的蛋白。 其中六种是核蛋白（EBNA），三种是膜蛋白，LMP1，LMP2A和LMP2B。 推测这9种蛋白质介导潜伏病毒感染或B。淋巴细胞增殖，因此正在进行深入研究。 除了附加体维持所需的EBNA1之外，LMP1和LMP2A是在EBV相关恶性肿瘤中一致检测到的潜伏表达蛋白，EBNA1和LMP2A信息是在来自携带潜伏EBV感染的个体的B淋巴细胞的PCR分析中检测到的仅有的EBV特异性信息. 鼻咽癌（NPC）发生在世界各地，但其特点是发病率的明显地理和人口差异。 虽然在欧洲人和北美高加索人中很少见，但NPC在中国南方和东南亚的发病率很高，可能占所有癌症的25%。 该肿瘤在其他中国人群、阿拉斯加爱斯基摩人和地中海非洲人中的发病率也有所增加。 鼻咽癌分为鳞状细胞癌（squamous cell carcinoma，SCC）、非角化性癌（nonkeratinizing carcinoma，NKC）和未分化癌（undifferentiated carcinoma，UC）。 最近的报道表明，所有形式的NPC均被EBV基因组的克隆群体感染。 在所有形式的NPC中，表达同一组EBV基因，即LMP1、LMP2A和EBNA1。 该研究计划分析EBNA1，LMP1和LMP2A在NPC发病机制中的作用，并可能为其他EBV相关恶性肿瘤提供信息。在四个具体目标中，我们建议分析表达EBNA 1、LMP 1和LMP 2A的角质形成细胞的体外表型，并建立转基因模型系统，以研究LMP 2A在NPC中的作用以及与LMP 1的可能合作。了解EBNA1、LMP1和LMP2A在NPC中的作用可能为NPC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。