Development of a mouse model to test HPV Antiviral compounds

开发小鼠模型来测试 HPV 抗病毒化合物

• 批准号: 10582890
• 负责人: ELLIOT J. ANDROPHY
• 金额: $ 19.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582890
• 关键词: Address; Animal Model; Animals; Antiviral Agents; Antiviral Therapy; Anus; Binding; Biological Models; Bypass; Carcinoma in Situ; Cell Culture Techniques; Cell Line; Cells; Cervical; Clinical Trials; Country; DNA biosynthesis; DNA cassette; Development; Diagnosis; Disease; Dysplasia; Early treatment; Episome; Epithelial Cells; Epithelium; Etiology; Excision; Genes; Genetic Transcription; Genital; Genitalia; Genome; Goals; Grant; HPV E7; High Prevalence; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immunodeficient Mouse; Infection; Infectious Skin Diseases; Interruption; Investigation; Lesion; Link; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Monitor; Mus; Mutation; Neomycin; Oncoproteins; Operative Surgical Procedures; Oral; Oral cavity; Oral mucous membrane structure; Oropharyngeal; Papilloma; Papillomavirus; Papillomavirus Transforming Protein E6; Pathogenesis; Persons; Pharmaceutical Preparations; Preclinical Drug Development; Prognosis; Proliferating; Proteins; RNA Splicing; Resistance; Resources; Risk Reduction; Rodent Model; Series; Skin; Species Specificity; Stress; System; Techniques; Testing; Therapeutic; Tissues; Topical application; Validation; Viral; Viral Genome; Viral Proteins; Virus Replication; Woman; antibiotic G 418; design; drug development; drug testing; drug-like compound; experimental study; first-in-human; in vivo; in vivo evaluation; keratinocyte; mouse model; novel; novel therapeutics; premalignant; programs; protein expression; research clinical testing; scale up; stability testing; therapeutic evaluation; tool; tumor; tumor progression

Project Summary/Abstract Papillomaviruses (PV) cause slowly proliferating epithelial tumors called warts or papillomas. These are very common infections of skin and the cervical, genital, anal, and oral mucosa. Infections with a subset of human and several animal PVs can progress to cervical, anogenital, and oropharyngeal malignancies. Because human PV infections are believed to be species specific, a fully representative model of HPV pathogenesis is not available in a common laboratoryanimal. There is no specifically antiviral therapy for early-stage HPV infection and for HPV-associated cancers. Currently, most treatments involve physical destruction or surgical removal of the infected and nearby tissues. In low resource countries, the lack of testing and scarce availability of surgical procedures results in very high prevalence of HPV-induced cancers. There is a critical unmet need for an in vivo system to test novel therapeutics aimed at eliminating HPV infection. A tractable mouse model to test antiviral agents specifically designed to interrupt HPV protein activities would have a major impact on pre-clinical drug development. The experiments proposed in this R21 grant will investigate the expression and maintenance of HPV-16 genomes in murine cell culture and in live mice. Several forms of HPV-16 genomes will be tested, including the creation of a mouse papillomavirus genome in which the native E6 and E7 genes are replaced by HPV- 16 E6 and E7. These oncoproteins are necessary for both viral genome replication and always expressed in HPV-associated malignancies and are therefore excellent targets for antiviral targeting. If HPV-16 is successfully propagated and the infection persists in mice, these murine models would be an important advance before clinical testing in human. Furthermore, this would also serve as a useful model to investigate the functions of HPV oncoproteins in genome maintenance and neoplastic progression. An antiviral treatment that cures early and persistent HPV-16 infections would reduce the risk and burden of progression to cancer that afflicts millions of people throughout the world.

项目概要/摘要 乳头瘤病毒 (PV) 会引起缓慢增殖的上皮肿瘤，称为疣或乳头状瘤。这些都是 非常常见的皮肤、宫颈、生殖器、肛门和口腔粘膜感染。感染的一个子集 人类和多种动物的真性红斑狼疮可进展为宫颈、肛门生殖器和口咽部恶性肿瘤。 由于人类 PV 感染被认为具有物种特异性，因此 HPV 的完全代表性模型 普通实验动物中尚无发病机制。 目前尚无针对早期 HPV 感染和 HPV 相关癌症的特异性抗病毒疗法。 目前，大多数治疗涉及物理破坏或手术切除感染者及其附近 组织。在资源匮乏的国家，缺乏检测和外科手术的稀缺导致 HPV 诱发的癌症患病率非常高。体内系统测试的需求尚未得到满足 旨在消除 HPV 感染的新疗法。用于测试抗病毒药物的易驯服小鼠模型 专门设计用于中断 HPV 蛋白活性的药物将对临床前药物产生重大影响 发展。 R21 资助中提出的实验将研究 HPV-16 的表达和维持 小鼠细胞培养物和活小鼠的基因组。将测试多种形式的 HPV-16 基因组，包括 创建小鼠乳头瘤病毒基因组，其中天然 E6 和 E7 基因被 HPV 取代 16 E6 和 E7。这些癌蛋白对于病毒基因组复制是必需的，并且总是在 因此，HPV 相关恶性肿瘤是抗病毒治疗的绝佳靶点。如果 HPV-16 是 成功繁殖并且感染在小鼠中持续存在，这些小鼠模型将是重要的 在人体临床测试之前取得进展。此外，这也可以作为一个有用的模型来研究 HPV 癌蛋白在基因组维护和肿瘤进展中的功能。抗病毒治疗 治愈早期和持续性 HPV-16 感染将降低进展为癌症的风险和负担 这困扰着全世界数百万人。