Murine Model for Hepatitis Antiviral/Anticancer Testing

描述(由申请人提供)：持续感染肝炎病毒、乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)构成了一个世界性的健康问题，在美国的流行率越来越高。持续的感染正在增加原发性肝细胞癌(HCC)的发生，这是一种没有有效治疗方法的癌症。因此，迫切需要能够模拟持续性肝炎感染和肝癌发生过程的实验系统。土拨鼠肝炎病毒(WHV)动物模型在抗病毒药物的测试和许可中是不可或缺的。这项应用的目的是验证一种新的基于小鼠的模型，用于大规模的抗病毒和抗癌测试。该模型通过复制持续感染阶段并在更短的时间范围内模拟小鼠的肝癌发生阶段，潜在地以更低的成本扩展了WHV模型的实用性。新的模型包括将土拨鼠或土拨鼠的肝细胞移植到免疫受损的含有尿激酶型纤溶酶原激活剂uPA转基因的“通用受体”转基因小鼠。这种基因创造了一种容易接受并允许移植的异种肝细胞生长的小鼠肝脏。最近，二肽基肽酶IV基因敲除等位基因(DPPIV-/-)被添加到受体小鼠的基因中，这使得能够以快速和简单的方式直接检测和定量移植的肝细胞。这一进展将简化肝癌发生的定量分析，并扩大该模型在抗癌应用中的应用。最近图帕亚肝细胞移植及其在模型中的乙肝病毒感染将被用来直接研究抗病毒和抗癌的治疗方法。所概述的实验是验证土拨鼠和土拨鼠移植系统(分别为“土拨鼠”和“土拨鼠”)进行大规模抗病毒和抗癌测试所需的实验。如果在未来的研究中证明该模型适用于丙型肝炎病毒感染，这些研究还将定位图帕亚姆鼠系统用于丙型肝炎病毒的研究。

DESCRIPTION (provided by applicant): Persistent infection with hepatitis viruses, hepatitis B virus (HBV) and hepatitis C virus, (HCV) constitute a worldwide health problem that is growing in prevalence in the United States. Persistent infections are increasing the occurrence of primary hepatocellular carcinoma, (HCC), a cancer for which there is no effective therapy. Therefore, there is an urgent need for experimental systems that can model the process of persistent hepatitis infection and hepatocarcinogenesis. The woodchuck hepatitis virus (WHV) animal model has been integral in the testing and licensing of antiviral drugs for HBV. The aim of this application is to validate a novel murine-based model for large scale antiviral and anticancer testing. The model extends the usefulness of the WHV model by duplicating the persistent infection phase and modeling the hepatocarcinogenesis phase in mice in a much shorter time frame and potentially at a lower cost. The new model involves the transplantation of woodchuck or tupaia hepatocytes into immunocompromised "universal recipient" transgenic mice that contain a urokinase plasminogen activator, uPA transgene. This gene creates a mouse liver that readily accepts and allows growth of transplanted xenogenic hepatocytes. Recently, a dipeptidyl peptidase IV knockout allele (DPPIV-/-) has been added to the genotype of the recipient mice and this allows direct detection and quantitation of transplanted hepatocytes in a rapid and simple manner. This advance will simplify quantitative hepatocarcinogenesis assays and expand the use of the model into anticancer applications. Recent demonstration of transplantation of tupaia hepatocytes and their HBV infection in the model will be exploited to directly study antiviral and anticancer treatments for HBV. The experiments outlined are those needed to validate the woodchuck, and tupaia transplantation systems ("woodmice and tupaiamice" respectively) for large scale antiviral and anticancer testing. These studies also will position the tupaiamouse system for HCV research if the model is shown to be suitable for HCV infection in future studies.