Human Papillomavirus and Polyomavirus Associated Malignancies.

人乳头瘤病毒和多瘤病毒相关恶性肿瘤。

• 批准号: 10601410
• 负责人: DENISE A. GALLOWAY
• 金额: $ 48.71万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601410
• 关键词: Human; Papillomavirus; Polyomavirus; Associated; Malignancies.

PROJECT SUMMARY/ABSTRACT My laboratory has been a leader in taking a broad based approach to studying the role that human papillomaviruses (HPVs) and human polyomaviruses (HPyVs) play in cancer. A major focus has been mechanistic studies to elucidate the contributions of the viral oncoproteins to malignancy. We have identified novel activities of the HPV E6 and E7 proteins including the induction of telomerase activity and inactivation of the p21 CDK inhibitor. For Merkel Cell polyomavirus (MCPyV) we have shown that it defines a new clade of PyVs that contains both primate and rodent PyVs encoding Middle T like proteins. We will explore new data showing that the Small T antigen can transform primary human fibroblasts and cooperate with Ras. We will develop novel mouse models to determine other genetic alterations that cooperate with the viral oncogenes to promote tumorigenicity. These models will be used in innovative ways to test new therapies. Additionally we have led, and participated in, collaborative studies with epidemiologists, statisticians and clinicians to understand the natural history of HPV infections and the host immune response to infection or vaccination. Our current studies focus on understanding the long term memory response to HPV infection to develop better insights into the mechanism of protection of the highly efficacious HPV vaccines, as well as to answer translational questions about optimal vaccine usage. Our overall goal has been, and will continue to be, to find new ways to better prevent, diagnose and treat HPV and HPyV infections that can lead to cancer. We are addressing significant issues, have a proven track record, a wealth of experience and reagents, terrific collaborators and an outstanding environment.

项目摘要/摘要 我的实验室在采用广泛的方法研究人类的角色方面一直处于领先地位 乳头瘤病毒(HPV)和人类多瘤病毒(HPyV)在癌症中发挥作用。一个主要的关注点是 阐明病毒癌蛋白在恶性肿瘤中的作用的机制研究。我们已经确定了 人乳头瘤病毒E6和E7蛋白的新活性，包括诱导端粒酶活性和失活 P21CDK抑制剂。对于默克尔细胞多瘤病毒(MCPyV)，我们已经证明它定义了一个新的分支 含有灵长类和啮齿类PYV的PYV，编码类中T蛋白。我们将探索新的数据 表明小T抗原可以转化原代人成纤维细胞，并与RAS协同作用。我们会 开发新的小鼠模型以确定与病毒癌基因协同作用的其他基因改变 促进致瘤性。这些模型将以创新的方式用于测试新的疗法。此外，我们 领导并参与了与流行病学家、统计学家和临床医生的合作研究 了解HPV感染的自然病史和宿主对感染或接种疫苗的免疫反应。 我们目前的研究集中在了解人乳头瘤病毒感染的长期记忆反应，以更好地发展 对高效HPV疫苗保护机制的见解以及回答 关于最佳疫苗使用的翻译问题。我们的总体目标一直是，并将继续是，找到 更好地预防、诊断和治疗可能导致癌症的HPV和HPyV感染的新方法。我们是 解决重大问题，有经过验证的记录，丰富的经验和试剂，非常棒 合作者和卓越的环境。