Function of the Epstein-Barr Virus EBNA-A3 Protein

EB 病毒 EBNA-A3 蛋白的功能

• 批准号: 7579862
• 负责人: Clare E Sample
• 金额: $ 25.12万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579862
• 关键词: Address; Affect; Affinity Chromatography; Amino Acids; B Cell Proliferation; B lymphocyte immortalization; B-Lymphocytes; Binding; Biochemical; Biological; Biological Assay; Burkitt Lymphoma; Cell Proliferation; Cells; Complex; Data; Development; Disease; Doctor of Philosophy; EBV-associated disease; EBV-associated malignancy; Epstein-Barr Virus Infections; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Herpesviridae; Highly Active Antiretroviral Therapy; Human Herpesvirus 4; Hypersensitivity; Immunobiology; In Vitro; Infection; Investigation; Knowledge; Laboratories; Lymphoma; Lymphomagenesis; Maintenance; Mediating; Messenger RNA; Mutate; National Institute of Allergy and Infectious Disease; Nuclear Protein; Nuclear Proteins; Oncogenic; Pathway interactions; Patients; Play; Population; Proteins; Regulation; Reporting; Research; Research Personnel; Response Elements; Role; Sampling; Support Groups; Transgenic Mice; Transplantation; Transplantation Immunology; Tumorigenicity; United States National Institutes of Health; Viral; Xenograft Model; base; c-myc Genes; cell growth; cell immortalization; epstein barr virus mediated immortalization; immortalized cell; in vivo; latent infection; mouse model; programs; promoter; protein complex; transcription factor; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The long term objective of the proposed research is to define the essential contribution of the latent Epstein- Barr virus (EBV) nuclear protein EBNA-3A to EBV-induced proliferation of B lymphocytes. EBV's ability to induce proliferation of primary B lymphocytes is believed to be central to the establishment of long term latency, and thus to the development of EBV-associated malignancies that typically occur years after primary infection. EBV-associated malignancies continue to occur in HIV-infected patients despite the advent of HAART, and thus the mechansims by which EBV establishes latency, as well as its role in development of disease, warrant futher investigation. An important target of EBNA-3A in EBV-immortalized cells is Jkappa, through which EBNA-3A represses transcription. Our preliminary studies, as well as data from other labs, strongly support our hypothesis that EBNA-3A also has Jkappa-independent functions. Although both Jkappa-dependent and -independent functions of EBNA-3A are likely to play significant roles in EBV-induced cellular proliferation, there are significant gaps in our knowledge regarding these additional pathways and the downstream effects. To elucidate the functions of EBNA-3A that contribute to EBV-mediated proliferation, we propose three integrated aims to address these gaps in our knowledge. Using transcriptional profiling, we have identified cellular genes regulated by EBNA-3A that are likely to be biologically relevant to EBV-induced proliferation. Under Aim 1, we will identify the pathways through which EBNA-3A regulates these genes, as well as determine their biological relevance to continued proliferation of EBV-immortalized B-cells. Under Aim 2, we will identify proteins through which EBNA-3A mediates its effects in EBV-transformed B lymphocytes by purification of EBNA-3A containing protein complexes. The finding that the EBNA-3 proteins are expressed in a subset of Burkitt lymphomas forms the basis for Aim 3, where we will determine whether EBNA-3A increases the tumorigenicity of BL cells using a xenograft model and whether it affects tumor development in a mouse model of BL. These three aims, supported byShiv A. Prasad, Ph.D. Chief, Transplantation Immunobiology Branch Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases - NIH 6610 Rockledge Dr., Rm. 3035 Bethesda, MD 20892-6601 our preliminary studies, should greatly extend our understanding of the biochemical functions of EBNA-3A, as well as the downstream effectors mediating its essential contribution to EBV-mediated immortalization of B lymphocytes, and thus the pathogenic potential of this oncogenic herpesvirus.

描述（由申请人提供）：拟议研究的长期目标是定义潜在的爱泼斯坦 - 巴尔病毒（EBV）核蛋白EBNA-3A对EBV诱导的B淋巴细胞增殖的基本贡献。 EBV诱导原发性B淋巴细胞增殖的能力被认为是建立长期潜伏期的核心，因此对于通常发生在原发性感染后几年的EBV相关恶性肿瘤的发展。尽管HAART出现了，但与EBV相关的恶性肿瘤继续发生在HIV感染的患者中，因此EBV建立潜伏期的机甲及其在疾病发展中的作用，保证了持续研究。 EBN-3A在EBV剥离细胞中的重要靶标是Jkappa，EBNA-3A通过它抑制转录。我们的初步研究以及其他实验室的数据强烈支持我们的假设，即EBNA-3A也具有与JKAPPA无关的功能。尽管EBNA-3A的JKAPPA依赖性和非依赖性功能都可能在EBV诱导的细胞增殖中起着重要作用，但我们的知识中存在很大的差距，这些差距和下游效应。为了阐明有助于EBV介导的增殖的EBNA-3A的功能，我们提出了三个综合目的，以解决我们知识中的这些差距。使用转录分析，我们已经确定了受EBNA-3A调控的细胞基因，这些基因可能与EBV诱导的增殖有关。在AIM 1下，我们将确定EBNA-3A调节这些基因的途径，并确定它们的生物学相关性，以与EBV免疫化B细胞的持续增殖。在AIM 2下，我们将通过纯化EBV淋巴细胞来鉴定EBNA-3a通过纯化EBNA-3A含有eBNA-3A含有蛋白质复合物的蛋白质。 EBNA-3蛋白在Burkitt淋巴瘤的一部分中表达的发现构成了AIM 3的基础，我们将确定EBNA-3A是否使用异种移植模型来确定EBNA-3A是否会增加BL细胞的肿瘤性，并且它是否影响BL小鼠模型中的肿瘤发展。这三个目标支持Byshiv A. Prasad博士。 移植免疫生物学部门酋长 过敏，免疫学和移植 国家过敏和传染病研究所-NIH 6610 Rockledge Dr.，RM。 3035 贝塞斯达（Bethesda），MD 20892-6601我们的初步研究，应大大扩展我们对EBNA-3A的生化功能的理解，以及介导其对EBV介导的B淋巴细胞不朽的基本贡献的下游效应子，从而介导了这种过敏性的症状症的致病潜力。