Genetic Analysis of EBV's Immortalizing Genes

描述（由申请人提供）：EB病毒（EBV）是一种肿瘤病毒，每年导致约10万人患淋巴瘤和癌症。我们已经开发并应用了EB病毒转化基因的遗传分析，重点是在感染的B淋巴细胞中EB病毒的潜伏膜蛋白1（LMP 1）。这些分析鉴定了由LMPV信号传导快速诱导的表型和细胞基因。我们建议扩展我们的遗传分析，通过识别它们诱导的表型和它们调节的细胞基因，进一步剖析LMP1，EB病毒核抗原1（EBNA1）和EBV的microRNA（miRNA）的转化功能。这些病毒转化基因都参与维持某些或所有EBV相关肿瘤的肿瘤表型。我们提出的遗传分析将有助于阐明这些病毒转化基因如何有助于肿瘤的维持。我们还将扩展我们对这些病毒基因的遗传分析，以剖析它们在受感染的上皮细胞中的功能。EBV引起的癌多于淋巴瘤，但以前在正常上皮细胞中的研究是棘手的。这些细胞现在易于感染，使我们能够表征其中的EBV转化基因。EBV在B淋巴细胞和上皮细胞中的功能不同。我们假设这些病毒转化基因调节B淋巴细胞和上皮细胞中不同的细胞基因，以介导EBV的不同致癌作用。对EBV转化基因的遗传分析将有助于确定它们对维持EBV相关淋巴瘤和癌的贡献。了解病毒对肿瘤维持的作用将有助于开发特异性抗病毒、抗肿瘤疗法。

DESCRIPTION (provided by applicant): Epstein-Barr Virus (EBV) is a tumor virus that causes lymphomas and carcinomas in approximately 100,000 people each year. We have developed and applied genetic analyses of EBV's transforming genes with this grant's prior support focusing on EBV's latent membrane protein 1 (LMP1) in infected B- lymphocytes. These analyses identified a phenotype and cellular genes induced rapidly by LMPVs signaling. We propose to extend our genetic analysis to dissect further transforming functions of LMP1, Epstein-Barr Nuclear Antigen 1 (EBNA1), and EBV's microRNAs (miRNAs) by identifying phenotypes they induce and cellular genes they regulate. These viral transforming genes are all implicated in maintaining tumor phenotypes in some or all of EBV-associated tumors. Our proposed genetic analyses will help to elucidate how these viral transforming genes contribute to tumor maintenance. We shall also extend our genetic analyses of these viral genes to dissect their functions in infected epithelial cells. EBV causes more carcinomas than lymphomas, but studies in normal epithelial cells formerly were intractable. These cells are now amenable to infection allowing us to characterize EBV's transforming genes in them. EBV functions differently in B-lymphocytes and epithelial cells. We hypothesize that these viral transforming genes regulate different cellular genes in B-lymphocytes and epithelial cells to mediate EBV's different oncogenic contributions. The proposed genetic analysis of EBV's transforming genes will help to identify their contributions to maintaining EBV-associated lymphomas and carcinomas. An understanding of viral contributions to tumor maintenance will allow development of specific anti-viral, anti-tumor therapies.