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: 6523869
• 负责人: Richard M Longnecker
• 金额: $ 25.77万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523869
• 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(Epstein-Barr Virus，EBV)可引起青少年传染性单核细胞增多症和艾滋病患者及器官移植免疫抑制患者的恶性B淋巴细胞增殖。EB病毒与非洲Burkitt淋巴瘤和鼻咽癌的病因学有关。在体外，EBV转化的、潜伏感染的B淋巴细胞含有EBV近似体和9种病毒编码蛋白。6个是核蛋白(EBNAs)，3个是完整的膜蛋白，即LMP1、LMP2A和LMP2B。这九种蛋白被认为是介导潜伏病毒感染或B.淋巴细胞增殖的媒介，因此正在进行密切的研究。除了EB病毒维持所需的EBNA1外，LMP1和LMP2a是在EBV相关恶性肿瘤中持续检测到的潜伏表达的蛋白质，而EBNA1和LMP2a信息是在对潜伏性EBV感染患者的B淋巴细胞进行PCR分析时检测到的唯一EBV特异性信息。鼻咽癌在世界范围内均有发生，但其发病具有明显的地域和人群差异。虽然鼻咽癌在欧洲人和北美高加索人中很少见，但它在中国南部和东南亚是高发的，在那里它可能占所有癌症的25%。这种肿瘤在其他中国人、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。鼻咽癌分为三种类型：鳞状细胞癌(SCC)、非角化性癌(NKC)和未分化癌(UC)。最近的报道表明，所有形式的鼻咽癌都统一感染EBV基因组的克隆性群体。在所有形式的鼻咽癌中，都表达相同的EBV基因集，即LMP1、LMP2A和EBNA1。这项研究拨款建议分析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在鼻咽癌中的作用及其与LMP1的可能合作。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。