An inbred mouse model for HCV infection, immunity andpathogenesis

HCV感染、免疫和发病机制的近交小鼠模型

• 批准号: 7820070
• 负责人: Charles M Rice
• 金额: $ 49.98万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820070
• 关键词: Acetoacetates; Address; Adverse effects; Affect; Animal Model; Animals; Antiviral Agents; Area; Biological Models; CD81 gene; Cells; Chronic; Complementary DNA; Development; Disease; Expenditure; Funding; Genes; Genome; Goals; Growth; HCV Animal Models; HCV Vaccine; Hepatitis C; Hepatitis C virus; Human; Human Virus; Hydrolase; Immunity; Inbred Mouse; Infection; Integration Host Factors; Interferons; Libraries; Life Cycle Stages; Light; Liver; Liver diseases; Modeling; Mouse Strains; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pan Genus; Population; Prevention; Proteins; RNA replication; Reagent; Recovery; Reporter; Screening procedure; System; Testing; Therapeutic; Tight Junctions; Transgenic Mice; Translational Research; Tropism; United States; Vaccines; Virus Replication; Work; base; drug testing; improved; in vivo; inhibitor/antagonist; insight; mouse model; novel; occludin; pre-clinical; public health relevance; receptor; viral RNA; virus pathogenesis

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational science and specific Challenge Topic, 15-DK-102: Develop improved animal models of NIDDK diseases. Hepatitis C virus (HCV) is an agent of chronic liver disease, and affects an estimated 3% of the global population. Preventative and therapeutic options are severely limited; there is currently no vaccine available and non-specific, interferon-based treatments are frequently ineffective and have significant side effects. A small animal model for HCV replication would significantly expedite antiviral compound development and pre-clinical testing. Unfortunately, the species tropism of HCV is limited to humans and chimpanzees. Here we propose to address the need for a mouse model of HCV pathogenesis by systematically identifying and overcoming the blocks to infection in this species. Recently, we used an iterative cDNA screening approach to discover occludin (OCLN) as an essential HCV entry factor. We further determined that this molecule, along with human CD81, is the major determinant of HCV species restriction at the level of entry. Here we propose to apply these findings to the development of transient and stably transgenic mice, with the aim of modeling HCV entry in vivo. We then propose to address blocks to HCV RNA replication in murine cells using similar library screening approaches, as well as novel selectable genomes. The development of an inbred mouse model for HCV infection and replication will provide a much-needed platform for in vivo HCV vaccine and drug testing. We are requesting funds to hire a technician to assist in this work, along with significant expenditures for reagents and supplies required for these studies. This proposal thereby furthers the aims of the Recovery Act while potentially making important progress towards a small animal model for HCV PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) infects an estimated 4 million in the United States, and 130 million worldwide. Treatment options are limited and often ineffective. We propose to develop a mouse model of HCV infection by sequentially overcoming each block to its growth in murine cells. Development of a robust small animal model for HCV would greatly expedite pre-clinical testing of prevention and therapeutic strategies.

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- dk -102：开发改进的NIDDK疾病动物模型。丙型肝炎病毒（HCV）是一种慢性肝病的病原体，影响着全球约3%的人口。预防和治疗选择严重有限；目前没有可用的疫苗，非特异性的基于干扰素的治疗往往无效，而且有明显的副作用。HCV复制的小动物模型将显著加快抗病毒化合物的开发和临床前试验。不幸的是，HCV的物种倾向仅限于人类和黑猩猩。在这里，我们建议通过系统地识别和克服该物种感染的障碍来解决HCV发病机制的小鼠模型的需求。最近，我们使用了一种迭代cDNA筛选方法来发现闭塞蛋白（occludin， OCLN）是HCV必不可少的进入因子。我们进一步确定，该分子与人CD81一起，是HCV进入水平限制物种的主要决定因素。在这里，我们建议将这些发现应用于瞬时和稳定的转基因小鼠的发展，目的是模拟HCV在体内的进入。然后，我们建议使用类似的文库筛选方法以及新的可选择基因组来定位小鼠细胞中HCV RNA复制的块。HCV感染和复制的近交小鼠模型的开发将为体内HCV疫苗和药物测试提供急需的平台。我们正在申请资金，以聘请一名技术人员协助这项工作，以及这些研究所需的试剂和用品的大笔支出。因此，该提案进一步推进了《康复法案》的目标，同时可能在HCV小动物模型方面取得重要进展