Cutaneous Human Papillomavirus as a Novel Model of Viral Oncogenesis

项目摘要： 新发传染病至少占所有人类病原体的12%。全球化程度提高， 其他因素导致世界卫生组织预测，新的传染性病原体将继续出现， 前所未有的速度。为了保护社会免受这些病原体的侵害，了解所有潜在的 传染性病原体引起疾病的机制。虽然病毒感染已知会导致15-20% 在癌症中，持续性β属人乳头瘤病毒（β-HPV）感染引起非黑素瘤皮肤癌。β-的 HPV在这些恶性肿瘤中的作用是通过一种新的机制，可以与新兴病原体共享。 具体而言，β-HPV感染作为辅助因子，沿着UV，阻断DNA修复并减少宿主基因组 忠诚由此产生的突变可以在不持续暴露于UV或β-HPV的情况下驱动肿瘤发生。此外 由于来自其他实验室的大量支持性流行病学、动物模型和细胞培养证据，PI和他的团队 研究组已经确定了β-HPV基因（β-HPV E6）减弱四种细胞DNA表达的能力， 修复因子β-HPV E6对修复的抑制主要源于病毒蛋白对细胞的降解， 转录因子p300。该提案定义了p300损失阻止细胞减轻的程度。 基因组不稳定事件，特别是发生在S期的事件。AIM 1询问β-HPV E6 抑制由DNA交联引发的信号传导事件。AIM 2定义了β-HPV E6的机制 双链DNA断裂修复受损。AIM 3决定β-HPV E6如何减弱 中心体重复研究团队结合了尖端技术和传统技术， 分子生物学和生物化学方法。无病毒系统证实了所有机制。选择性力量 （依赖于宿主复制因子和对阳光暴露细胞的向性），这使得β- HPV破坏细胞周期调控和DNA修复并非β-HPV所独有。因此，p300失活由其他 新的皮肤病毒将是致癌潜力的良好标志物。本研究的总体目标是 了解p300不稳定的致突变潜力，以改善对新出现病毒的风险评估。 更具体地说，对于β-HPV，预期结果具有预防意义，因为目前FDA批准的HPV 疫苗技术可以适用于靶向β-HPV，并且可以开发β-HPV特异性抑制剂， 添加到用于阻挡紫外线的制剂中（例如防晒霜）。

Project Summary: Emerging infectious diseases account for at least 12% of all human pathogens. Increased globalization among other factors led the World Health Organization to predict that novel infectious agents will continue to appear at an unprecedented rate. To protect society against these pathogens, it is essential to know all of the potential mechanisms by which infectious agents can cause disease. While viral infections are known to cause 15-20% of cancers, persistent genus β human papillomavirus (β-HPV) infections cause non-melanoma skin cancers. β- HPV's role in these malignancies is through a novel mechanism that could be shared with emerging pathogens. Specifically, β-HPV infections act as co-factor that along with UV, blocks DNA repair and reduces host genome fidelity. The resulting mutations can drive tumorigenesis without continued exposure to UV or β-HPV. In addition to abundant supportive epidemiological, animal model, and cell culture evidence from other labs, the PI and his group have established the ability of a β-HPV gene (β-HPV E6) to attenuate the expression of four cellular DNA repair factors. β-HPV E6's inhibition of repair stem primarily from the viral protein's degradation of a cellular transcription factor, p300. This proposal defines the extent that the p300 loss prevents cells from mitigating genome destabilizing events, particularly events occurring during S-phase. AIM1 interrogates β-HPV E6's inhibition of signaling events triggered by DNA crosslinks. AIM2 defines the mechanisms of β-HPV E6's impairment of double strand DNA break repair. AIM3 determines how β-HPV E6 attenuates the regulation of centrosome duplication. The research team uses a combination of cutting edge techniques as well as traditional molecular biology and biochemical approaches. Virus-free systems confirm all mechanisms. The selective forces (dependence on host replication factors and a tropism for sun-exposed cells) that make it advantageous for β- HPV to disrupt cell cycle regulation and DNA repair are not unique to β-HPV. Thus, p300 inactivation by other novel cutaneous viruses would be a good marker of oncogenic potential. The overall goal of this study is to understand the mutagenic potential of p300 destabilization to improve risk assessment of emerging viruses. More specific to β-HPV, the expected results have preventative implications as the current FDA-approved HPV vaccine technology could be adapted to target β-HPV and β-HPV specific inhibitors could be developed and added to formulations used to block UV light (e.g. sunscreen).