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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘