Murine Model for Hepatitis Antiviral/Anticancer Testing

描述（由申请人提供）：持续感染肝炎病毒，乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）构成了一个全球性的健康问题，在美国越来越流行。持续感染增加了原发性肝细胞癌（HCC）的发生率，HCC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HBV抗病毒药物的测试和许可中是不可或缺的。本申请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。该模型通过在更短的时间框架内以更低的成本复制小鼠的持续感染阶段和肝癌发生阶段，扩展了WHV模型的实用性。新模型涉及将土拨鼠或土拨鼠肝细胞移植到含有尿激酶纤溶酶原激活剂（uPA）转基因的免疫受损的“通用受体”转基因小鼠中。这种基因产生的小鼠肝脏能够接受并允许移植的异种肝细胞生长。最近，一个二肽基肽酶IV敲除等位基因（DPPIV-/-）被添加到受体小鼠的基因型中，这使得可以快速简单地直接检测和定量移植肝细胞。这一进展将简化定量肝癌发生分析，并将该模型扩展到抗癌应用中。近期在该模型中移植tupaia肝细胞及其HBV感染的研究将被用于直接研究HBV的抗病毒和抗癌治疗。概述的实验是验证土拨鼠和土拨鼠移植系统（分别为“木鼠和土拨鼠”）用于大规模抗病毒和抗癌测试所需的实验。如果该模型在未来的研究中被证明适用于HCV感染，这些研究也将为HCV研究定位tupaiamouse系统。

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.