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.

这项研究的基础是我们的发现，即EB病毒（EBV）的EBNA 1蛋白对正常和肿瘤来源的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，有多个顺式作用元件在EB病毒的基因组，可以有助于染色体外复制。它还包括与Compton和Lambert博士的合作研究，以检查卡波西肉瘤病毒（KSHV）和人乳头瘤病毒16型（HPV-16）的染色体外复制。我们将确定和表征EBV DNA的顺式作用元件，而不是其二分体对称元件（DS），可以支持DNA合成的起始，并研究KSHV DNA中的类似元件。我们 特别感兴趣的是阐明病毒复制子在增殖细胞中维持的机制，并将研究EBNA 1对EBV衍生质粒的维持以及E2蛋白对HPV 16衍生质粒维持的可能贡献。这些研究是由以下假设驱动的：抑制人类肿瘤病毒的维持功能应允许开发针对其相关肿瘤的合理、有效的疗法。EBV的EBNA 1和KSHV的LANA 1均抑制细胞凋亡。我们建议确定它们这样做的机制。阻断这种抑制也可能对治疗EBV和KSHV相关肿瘤有治疗益处。