EBV's Plasmid Replicon: Its Synthesis, Partitioning, and Maintenance of Tumors

EBV 的质粒复制子：其合成、分区和肿瘤的维持

• 批准号: 8208237
• 负责人: WILLIAM M. SUGDEN
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-23 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208237
• 关键词: AIDS-Related Lymphoma; Acquired Immunodeficiency Syndrome; Adult; Africa; Apoptosis; B-Cell Neoplasm; B-Lymphocytes; Burkitt Lymphoma; Carcinoma; Cells; Childhood Burkitt' s Lymphoma; China; Couples; Coupling; Dependence; Event; Genes; Genome; Genomics; Goals; Growth; Hodgkin Disease; Human; Human Herpesvirus 4; Immunocompromised Host; Infection; Life; Lymphoma; Lymphoproliferative Disorders; Maintenance; Malignant - descriptor; Maps; Measures; Methods; Nasopharynx Carcinoma; Oncogenic Viruses; Patients; Phenotype; Plasmids; Proliferating; Property; Proteins; Regulator Genes; Replicon; Role; S Phase; Site; Time; Transplantation; Viral; Viral Genes; Viral Genome; Viral Proteins; Work; antitumor drug; cis acting element; fascinate; human DNA; infected B cell; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; neoplastic cell; prevent; public health relevance; replicator; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Epstein-Barr Virus (EBV) is a human tumor virus causally associated with multiple types of lymphomas and carcinomas. Its genome is maintained in both normal and malignant proliferating cells as a plasmid. We have studied EBV's plasmid replicon to elucidate both its synthesis and partitioning and its contributions to EBV's tumorigenesis. Earlier we identified its cis-acting element, oriP, and its sole viral trans-acting protein, EBNA1. We recently developed a method to visualize EBV plasmid replicons in live cells, which has uncovered several fascinating properties. For example, they are duplicated each S-phase only 84% of the time; and they encode a non-random mechanism of partitioning which spatially couples partitioning to their synthesis. We propose now in Aim 1 to characterize the synthesis and partitioning of EBV genomes early after infection of primary B-cells to understand how these events contribute to EBV's establishing its stable infection of these cells. We shall in Aim 2 dissect the mechanism of EBV's partitioning to understand its coupling to its synthesis. We have also recently discovered that inhibiting EBV's plasmid replicon by inhibiting EBNA1 induces apoptosis in normal and malignant, EBV-infected B-cells. We shall extend these findings in Aim 3 to EBV-associated tumors in immunocompromised hosts such as AIDS patients. In particular, we propose to investigate the mechanisms by which EBV prevents apoptosis in these infected, malignant B-cells and identify the viral genes that allow these tumor cells to survive. PUBLIC HEALTH RELEVANCE: All of these studies will reveal the mechanisms by which EBV replicates as a plasmid in infected cells. In addition to indicating how inhibiting EBNA1 would be therapeutically beneficial, they should also identify additional targets for developing anti-viral anti-tumor drugs.

描述（由申请人提供）： Epstein-Barr 病毒（EBV）是一种与多种类型的淋巴瘤和癌症有因果关系的人类肿瘤病毒。其基因组以质粒形式保留在正常和恶性增殖细胞中。我们研究了 EBV 的质粒复制子，以阐明其合成和分配及其对 EBV 肿瘤发生的贡献。早些时候，我们鉴定了其顺式作用元件 oriP 及其唯一的病毒反式作用蛋白 EBNA1。我们最近开发了一种在活细胞中可视化 EBV 质粒复制子的方法，该方法发现了一些令人着迷的特性。例如，每个 S 期它们只有 84% 的时间重复；它们编码了一种非随机的划分机制，该机制在空间上将划分与其合成耦合起来。现在，我们在目标 1 中建议在原代 B 细胞感染后早期表征 EBV 基因组的合成和划分，以了解这些事件如何有助于 EBV 建立对这些细胞的稳定感染。我们将在目标 2 中剖析 EBV 的分配机制，以了解其与其合成的耦合。我们最近还发现，通过抑制 EBNA1 来抑制 EBV 的质粒复制子，会诱导正常和恶性、EBV 感染的 B 细胞凋亡。我们将目标 3 中的这些发现扩展到免疫功能低下宿主（例如 AIDS 患者）中的 EBV 相关肿瘤。特别是，我们建议研究 EBV 阻止这些受感染的恶性 B 细胞凋亡的机制，并鉴定允许这些肿瘤细胞存活的病毒基因。 公共健康相关性：所有这些研究都将揭示 EBV 在受感染细胞中作为质粒复制的机制。除了表明抑制 EBNA1 如何在治疗上有益之外，他们还应该确定开发抗病毒抗肿瘤药物的其他靶点。