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: 10461103
• 负责人: DENISE A. GALLOWAY
• 金额: $ 101.88万
• 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/10461103
• 关键词: Address; Data; Diagnosis; Environment; Epidemiologist; Fibroblasts; Goals; Human; Human Activities; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Immune response; Infection; Laboratories; Lead; Malignant Neoplasms; Merkel Cells; Modeling; Mutation; Natural History; Oncoproteins; Other Genetics; Play; Polyomavirus; Polyomavirus Infections; Primates; Proteins; Reagent; Rodent; Role; Small T Antigen; Telomerase; Testing; Tumorigenicity; Vaccination; Vaccines; Viral; Viral Oncogene; base; experience; inhibitor; innovation; insight; long term memory; mouse model; novel; novel therapeutics; prevent; response; virus related cancer

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.

项目概要/摘要 我的实验室在采取广泛的方法来研究人类的作用方面一直处于领先地位。 乳头瘤病毒 (HPV) 和人类多瘤病毒 (HPyV) 与癌症有关。一个主要焦点是 阐明病毒癌蛋白对恶性肿瘤的作用的机制研究。我们已经确定 HPV E6 和 E7 蛋白的新活性包括诱导端粒酶活性和灭活 p21 CDK 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进化枝 PyV 包含编码中 T 样蛋白的灵长类和啮齿类 PyV。我们将探索新数据 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。我们将 开发新的小鼠模型来确定与病毒癌基因合作的其他遗传改变 促进致瘤性。这些模型将以创新的方式用于测试新疗法。另外我们 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 感染的自然史以及宿主对感染或疫苗接种的免疫反应。 我们目前的研究重点是了解对 HPV 感染的长期记忆反应，以便更好地发展 深入了解高效HPV疫苗的保护机制，并解答 有关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寻找 更好地预防、诊断和治疗可导致癌症的 HPV 和 HPyV 感染的新方法。我们是 解决重大问题，拥有良好的记录，丰富的经验和试剂，非常棒 合作者和优秀的环境。