Function of the Epstein-Barr Virus EBNA-A3 Protein

EB 病毒 EBNA-A3 蛋白的功能

• 批准号: 7216771
• 负责人: Clare E Sample
• 金额: $ 23.23万
• 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/7216771
• 关键词: Address; Affect; Affinity Chromatography; Allergy and Immunology; 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; 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; Simplexvirus; Support Groups; Transgenic Organisms; Transplantation; 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; 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）：所提议研究的长期目标是确定潜在的 Epstein-Barr 病毒 (EBV) 核蛋白 EBNA-3A 对 EBV 诱导的 B 淋巴细胞增殖的重要贡献。 EBV 诱导原代 B 淋巴细胞增殖的能力被认为是长期潜伏期建立的核心，因此也是 EBV 相关恶性肿瘤发生的核心，通常在原发感染数年后发生。尽管出现了HAART，EBV相关恶性肿瘤仍继续发生在HIV感染者中，因此EBV建立潜伏期的机制及其在疾病发展中的作用值得进一步研究。 EBV 永生化细胞中 EBNA-3A 的一个重要靶标是 Jkappa，EBNA-3A 通过 Jkappa 抑制转录。我们的初步研究以及其他实验室的数据有力地支持了我们的假设，即 EBNA-3A 也具有独立于 Jkappa 的功能。尽管 EBNA-3A 的 Jkappa 依赖性和独立性功能可能在 EBV 诱导的细胞增殖中发挥重要作用，但我们对这些额外途径和下游效应的了解还存在显着差距。为了阐明 EBNA-3A 促进 EBV 介导的增殖的功能，我们提出了三个综合目标来解决我们的知识空白。通过转录分析，我们已经鉴定出受 EBNA-3A 调节的细胞基因，这些基因可能与 EBV 诱导的增殖具有生物学相关性。在目标 1 下，我们将确定 EBNA-3A 调节这些基因的途径，并确定它们与 EBV 永生化 B 细胞持续增殖的生物学相关性。在目标 2 下，我们将通过纯化含有 EBNA-3A 的蛋白质复合物来鉴定 EBNA-3A 在 EBV 转化的 B 淋巴细胞中介导其作用的蛋白质。 EBNA-3 蛋白在 Burkitt 淋巴瘤亚群中表达的发现构成了目标 3 的基础，我们将使用异种移植模型确定 EBNA-3A 是否会增加 BL 细胞的致瘤性，以及它是否会影响 BL 小鼠模型中的肿瘤发展。这三个目标得到了 Shiv A. Prasad 博士的支持。 移植免疫生物学分部主任 过敏、免疫学和移植科 美国国家过敏症和传染病研究所 - NIH 6610 Rockledge Dr.，Rm。 3035 Bethesda, MD 20892-6601 我们的初步研究应该极大地扩展我们对 EBNA-3A 生化功能的理解，以及介导其对 EBV 介导的 B 淋巴细胞永生化的重要贡献的下游效应器，以及这种致癌疱疹病毒的致病潜力。