Mouse Model of Human Papillomavirus Pathogenesis

人乳头瘤病毒发病机制的小鼠模型

基本信息

批准号：
9904588
负责人：
PAUL F. LAMBERT
金额：
$ 46.82万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904588
关键词：
Address Animal Model Animals Anogenital cancer Antiviral Therapy Area Binding Binding Sites Biological Assay C-terminal Cancer Etiology Cell Cycle Cells Cervix carcinoma Chronic Complement Cutaneous Development Epidermodysplasia Verruciformis Epithelial Epithelium Etiology Genetic Transcription Genetically Engineered Mouse Genome Head and Neck Cancer House mice Human Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Human papillomavirus 18 Hyperplasia Immune signaling Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunosuppression India Infection Inherited Laboratories Laboratory mice Length Lesion Life Cycle Stages Link MADH2 gene Malignant Neoplasms Mediating Modeling Mouse Strains Mus Mutate Oncogenic Organ Transplantation Papilloma Papillomavirus Papillomavirus Infections Pathogenesis Pathway interactions Patients Population Preventive vaccine Proteins Proteomics RB1 gene Reporting Research Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Skin Skin Cancer Source Squamous Epithelium Stimulator of Interferon Genes Sun Exposure TRIM25 gene Testing Transforming Growth Factor beta Transgenic Mice UV Radiation Exposure Ultraviolet Therapy Vaccination Vaccines Viral Viral Pathogenesis Withdrawal Work base carcinogenesis cellular targeting combat experimental study high risk high risk population human model in vivo insight keratinocyte differentiation mouse model mucosal site mutant programs retinoblastoma tumor suppressor skin disorder skin lesion skin squamous cell carcinoma viral carcinogenesis

项目摘要

Human papillomavirus (HPV) infections cause approximately 5% of all human cancers. A group of “high-risk” alpha-HPVs are etiologic agents of cervical carcinoma, other anogenital cancers and as well as head and neck cancers. The beta-HPVs cause cutaneous squamous cell carcinomas (cSCCs) in patients with a rare hereditary skin disorder, epidermodysplasia verruciformis (EV), and in the rapidly growing population of organ-transplant and other chronically immunosuppressed patients. The gamma-HPVs have also been detected in cSCCs. Even though prophylactic vaccines that protect from infections with most cancer-associated alpha-HPVs are on the market, US vaccination rates have remained low, and because cancers arise years to decades after the initial infection, vaccination will not have an immediate impact on HPV cancer rates. Moreover, these vaccines do not offer protection from beta- and gamma-HPV infections and, hence, they will not impact cSCCs triggered by these HPVs. The E6 and E7 proteins encoded by the cancer-associated alpha- and beta-HPVs have oncogenic activities and function by binding to and functionally subverting host cellular signaling proteins. Because HPVs do not replicate in heterologous hosts, there have only been very few studies that probed the relevance of papillomavirus E6 and E7 cellular targets for viral pathogenesis and carcinogenesis in vivo. The discovery of Mus musculus Papillomavirus 1 (MmuPV1), which infects common laboratory mouse strains, finally allows papillomavirus pathogenesis and carcinogenesis studies in vivo and in a genetically tractable host. This proposal leverages the expertise of the Lambert group who has established an MmuPV1 infection/pathogenesis model for cutaneous and mucosal sites and the Munger lab who has identified MmuPV1 E6- and E7-associated cellular proteins and validated many of these interactions in cell-based assays. Our proposal is based on the hypothesis that MmuPV1 is a model to investigate HPV pathogenesis and carcinogenesis, and these insights will be key to identifying targets for antiviral therapy. We will investigate the importance of MmuPV1 E6 inhibiting NOTCH and TGF-beta signaling, and E7 subverting the retinoblastoma tumor suppressor RB1, as well as E6 and E7 mediated subversion of innate immune signaling by the RIG-I/MAVS and cGAS/STING, respectively, for cutaneous pathogenesis and carcinogenesis.

人乳头瘤病毒（HPV）感染约为所有人类癌症的5％。一组“高风险”α-HPV是宫颈癌，其他肛门生殖器癌以及头颈癌的病因。 β-HPV引起皮肤鳞状细胞癌（CSCC），患有罕见的遗传性皮肤疾病，表皮发育不良的患者（EV），以及在迅速增长的组织 - 转移剂和其他慢性病免疫抑制的患者中。在CSCC中也检测到了γ-HPV。尽管预防性疫苗免受大多数与癌症相关的α-HPV的感染的预防性疫苗，但美国疫苗的发生率仍然很低，并且由于癌症初次感染后数十年出现了几年，因此疫苗不会直接对HPV癌症率产生直接影响。此外，这些疫苗不提供防止β和伽玛 - HPV感染的保护，因此，它们不会影响这些HPV触发的CSCC。由癌症相关的α-和β-HPV编码的E6和E7蛋白通过与宿主细胞信号蛋白结合并颠覆宿主细胞信号蛋白，具有致癌活性和功能。由于HPV在异源宿主中没有复制，因此只有很少的研究证明了乳头瘤病毒E6和E7细胞靶标与体内病毒发病机理和致癌作用的相关性。感染了常见的实验室小鼠菌株的Mus musculus乳头瘤病毒1（MMUPV1）的发现，最终使乳头瘤病毒发病机理和体内和可遗传宿主中的乳头瘤病毒发病机理和癌变研究。该提案利用了兰伯特集团的专业知识，该集团已经为皮肤和粘膜部位建立了MMUPV1感染/发病机制模型，以及已经鉴定出MMUPV1 E6-和E7相关的细胞蛋白的Munger Lab，并在基于细胞的分析中验证了许多这些相互作用。我们的建议基于以下假设：MMUPV1是研究HPV发病机理和癌变的模型，这些见解将是识别抗病毒治疗靶标的关键。我们将研究MMUPV1 E6抑制Notch和TGF-BETA信号传导的重要性，E7颠覆了视网膜母细胞瘤肿瘤抑制RB1，以及E6和E7通过RIG-I/MAVS和CGAS/CGAS/CGAS/STING和CATENESESSESTON和CARCANESSESTONSENGENGENENGENGENGENENGENGENGENGENGENGENGENGEN和CARCANESSENCONS，ERIG-I/MAV和CGAS/MAV和CGAS/MAV和CGAS/MAV和CGAS和CGAS的介导的颠覆。