Human Papillomavirus and Polyomavirus Associated Malignancies.

项目概要/摘要 我的实验室一直是一个领导者，在采取广泛的基础上的方法来研究人类的作用， 乳头瘤病毒（HPV）和人多瘤病毒（HPyV）在癌症中起作用。一个主要的重点是 机制研究，以阐明病毒癌蛋白的恶性肿瘤的贡献。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），我们已经表明，它定义了一个新的进化枝， PyV，其含有编码中T样蛋白的灵长类和啮齿类PyV。我们将探索新的数据 表明小T抗原可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，以确定与病毒致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感染的自然史和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HPV感染的长期记忆反应，以更好地发展 深入了解高效HPV疫苗的保护机制，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 解决重大问题，有良好的业绩记录，丰富的经验和试剂， 合作伙伴和出色的环境。

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.