基本信息
浏览量:132
职业迁徙
个人简介
Research Interests
For 37 years, the lab of Tom Broker and myself has investigated the pathobiology of the prevalent mucosotropic human papillomaviruses (HPVs). Low-risk HPV types 6 and 11 cause most genital warts and all recurrent respiratory papillomatosis. Infections by high-risk HPVs, including types 16 and 18, can lead to neoplastic dysplasias and cancers in the anogenital tract of women and men. After discovering that HPV DNA amplifies in differentiating squamous epithelia, we optimized organotypic raft cultures of primary human keratinocytes (PHKs) grown at the liquid medium/air interface to recapitulate a full-thickness squamous epithelium. We characterized the interactions among HPV oncoproteins E6 and E7 and host proteins and pathways. Notably, E7 reactivates S-phase reentry in differentiated keratinocytes necessary to support viral DNA amplification by destabilizing p130, a pRBrelated protein. We then developed a system which achieved a robust reproductive program and produced high titers of infectious virions in PHK raft cultures using cloned wild type HPV-18 DNA. We demonstrated that HPV induces and is dependent on DNA damage responses for efficient viral DNA amplification. We showed that a key function of E6 is to inactivate the p53 tumor suppressor, enabling high level viral DNA amplification. Mutational analyses are being conducted to study the viral replicative helicase E1 and the small membrane E5 protein, which enhances signal transduction by growth factor receptors. Finally, the productive raft culture is being use as a platform to examine the effects of a number of pathway-specific inhibitors on viral DNA amplification. Very effective inhibitors have been identified, some of which are in clinical trials for various cancers. Our research suggests that it is feasible to repurpose approved inhibitors to treat HPV infections. Investigation of anti-HPV inhibitors arefurther described by N. Sanjib Banerjee, who has broadened our efforts in drug discovery to include inhibitors to treat cervical cancer.
For 37 years, the lab of Tom Broker and myself has investigated the pathobiology of the prevalent mucosotropic human papillomaviruses (HPVs). Low-risk HPV types 6 and 11 cause most genital warts and all recurrent respiratory papillomatosis. Infections by high-risk HPVs, including types 16 and 18, can lead to neoplastic dysplasias and cancers in the anogenital tract of women and men. After discovering that HPV DNA amplifies in differentiating squamous epithelia, we optimized organotypic raft cultures of primary human keratinocytes (PHKs) grown at the liquid medium/air interface to recapitulate a full-thickness squamous epithelium. We characterized the interactions among HPV oncoproteins E6 and E7 and host proteins and pathways. Notably, E7 reactivates S-phase reentry in differentiated keratinocytes necessary to support viral DNA amplification by destabilizing p130, a pRBrelated protein. We then developed a system which achieved a robust reproductive program and produced high titers of infectious virions in PHK raft cultures using cloned wild type HPV-18 DNA. We demonstrated that HPV induces and is dependent on DNA damage responses for efficient viral DNA amplification. We showed that a key function of E6 is to inactivate the p53 tumor suppressor, enabling high level viral DNA amplification. Mutational analyses are being conducted to study the viral replicative helicase E1 and the small membrane E5 protein, which enhances signal transduction by growth factor receptors. Finally, the productive raft culture is being use as a platform to examine the effects of a number of pathway-specific inhibitors on viral DNA amplification. Very effective inhibitors have been identified, some of which are in clinical trials for various cancers. Our research suggests that it is feasible to repurpose approved inhibitors to treat HPV infections. Investigation of anti-HPV inhibitors arefurther described by N. Sanjib Banerjee, who has broadened our efforts in drug discovery to include inhibitors to treat cervical cancer.
研究兴趣
论文作者统计合作学者相似作者
按年份排序按引用量排序主题筛选期刊级别筛选合作者筛选合作机构筛选
时间
引用量
主题
期刊级别
合作者
合作机构
作者统计
合作学者
合作机构
D-Core
- 合作者
- 学生
- 导师
数据免责声明
页面数据均来自互联网公开来源、合作出版商和通过AI技术自动分析结果,我们不对页面数据的有效性、准确性、正确性、可靠性、完整性和及时性做出任何承诺和保证。若有疑问,可以通过电子邮件方式联系我们:report@aminer.cn