Project 5

项目5

• 批准号: 6752164
• 负责人: WILLIAM M. SUGDEN
• 金额: $ 26.79万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-29 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752164
• 关键词: B lymphocyte; Epstein Barr virus; cell growth regulation; cell line; cell transformation; gene expression; genetic regulatory element; genetic transcription; human herpesvirus 8; human papillomavirus; human subject; laboratory rabbit; leukocyte activation /transformation; lymphocyte proliferation; oncogenes; oncoproteins; viral carcinogenesis; virus genetics; virus protein; virus replication

The proposed research builds on our findings that the EBNA1 protein of Epstein-Barr Virus (EBV) is pivotal to the proliferation and survival of normal and tumor-derived EBV-positive cells. It builds on our and other researchers' findings that there are multiple cis-acting elements within EBV's genome that can contribute to extrachromosomal replication. It also encompasses collaborative studies with Drs. Compton and Lambert to examine extrachromosomal replication of Kaposi's sarcoma virus (KSHV) and human papillomavirus type 16 (HPV-16). We shall identify and characterize cis-acting elements of EBV DNA other than its dyad symmetry element (DS) that can support initiation of DNA synthesis and study similar elements in KSHV DNA. We are particularly interested in elucidating the mechanisms by which viral replicons are maintained in proliferating cells and shall study the maintenance of EBV-derived plasmids by EBNA1 and the possible contributions of the E2 protein to the maintenance of HPV16-derived plasmids. These studies are driven by the hypothesis that the inhibition of maintenance functions of human tumor viruses should permit the development of rational, effective therapies for their associated tumors. Both EBNA1 of EBV and LANA1 of KSHV inhibit apoptosis. We propose to identify the mechanisms by which they do so. It is possible that blocking this inhibition would also be therapeutically beneficial for treating EBV- and KSHV-associated tumors.

拟议的研究建立在我们的发现之上，即 Epstein-Barr 病毒 (EBV) 的 EBNA1 蛋白对于正常和肿瘤来源的 EBV 阳性细胞的增殖和存活至关重要。它建立在我们和其他研究人员的发现之上，即 EBV 基因组内存在多个可促进染色体外复制的顺式作用元件。它还包括与博士的合作研究。 Compton 和 Lambert 检查卡波西肉瘤病毒 (KSHV) 和 16 型人乳头瘤病毒 (HPV-16) 的染色体外复制。我们将鉴定和表征 EBV DNA 中除二分体对称元件 (DS) 之外的可支持 DNA 合成启动的顺式作用元件，并研究 KSHV DNA 中的类似元件。我们是 对阐明病毒复制子在增殖细胞中维持的机制特别感兴趣，并应研究 EBNA1 对 EBV 衍生质粒的维持以及 E2 蛋白对 HPV16 衍生质粒维持的可能贡献。这些研究的驱动因素是，抑制人类肿瘤病毒的维持功能应该能够为其相关肿瘤开发合理、有效的疗法。 EBV的EBNA1和KSHV的LANA1均抑制细胞凋亡。我们建议确定他们这样做的机制。阻断这种抑制也可能对治疗 EBV 和 KSHV 相关肿瘤有治疗作用。