Development of Novel In Vitro Models for Hepatitis B Virus and Hepatitis C Virus Infection and Replication

乙型肝炎病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)是嗜肝病毒，感染后可引起肝脏急慢性疾病。全球已有多达20亿人感染了乙肝病毒。在这些人中，约有3.5亿人患上了慢性乙肝，每年死亡人数超过60万人(Ganem和Prince，2004年)。据估计，全球丙型肝炎病毒感染人数超过1.7亿人，每年有超过35万人死于丙型肝炎相关肝病(Te和Jensen，2010年)。尽管已经开发了抗乙肝病毒和抗丙型肝炎病毒的药物来治疗患者，但乙肝病毒或丙型肝炎病毒很难完全根除。此外，长期药物制度对患者和医疗保健提供者来说都很昂贵。因此，慢性乙肝病毒或丙型肝炎病毒感染是导致发病率和死亡率的主要原因，因此存在更好地了解病毒感染和复制的重大医学需求，这将导致更有效的药物的开发。关于乙肝病毒或丙型肝炎病毒感染和生命周期的详细研究一直受到寻找和培养人类黄金标准模型-原代人类肝细胞(PHHs)的困难。PHHs是从低质量的组织碎片中分离出来的稀缺资源，在有限的体外培养时间(2-4天)后失去功能。因此，寻求和开发了替代模式。动物肝细胞、肝细胞癌细胞系或转基因小鼠模型有助于了解乙肝和丙型肝炎的发病机制。然而，尽管它们取得了成功，但这些模型仍存在一些缺点，因此它们没有正确地模拟体内的情况。该项目将研究一种替代的和可再生的肝细胞来源，这些肝细胞有可能克服以前的限制，未来可能提供一个平台来筛选治疗乙肝和丙型肝炎感染者的新药。参考文献：Ganem D和Prince AM(2004)N Engl J Med，350,1118-1129，Te HS和Jensen DM(2010)Clin liver Dis，14，1-21，vi.

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are hepatotropic viruses that can cause acute and chronic diseases in liver after infection. Up to 2 billion people have been infected by HBV in the world. Among those approximately 350 million of people have developed chronic Hepatitis B and the annual death is greater than 600,000 (Ganem and Prince, 2004). Global HCV infection has been estimated to be in excess of 170 million individuals, with more than 350,000 deaths per annum due to HCV-related liver disease (Te and Jensen, 2010). Although anti-HBV and anti-HCV drugs have been developed to treat patients, HBV or HCV are hard to completely eradicate. In addition, long-term drug regimes are expensive to both patients and healthcare providers. Chronic HBV or HCV infection is therefore a major cause of morbidity and mortality and major medical requirement exists to develop a better understanding of viral infection, replication which will lead to the development of more effective medicines.Detailed research on HBV or HCV infection and lifecycle has been hampered by difficulties in sourcing and culturing the human gold standard model, primary human hepatocytes (PHHs). PHHs are a scarce resource that are isolated from low quality tissue fragment and lose function following limited period of in vitro culture (2-4 days). Therefore, alternative models have been sought and developed. Animal hepatocytes, HCC cell lines, or transgenic mouse models have contributed to understanding the pathogenesis of HBV and HCV. However, despite their successes there are a number of shortcomings in those models and as a consequence they do not properly model the in vivo situation. The project proposed will examine an alternative and renewable source of hepatocytes which have the potential to overcome previous limitations, and in the future may offer a platform to screen for novel medicines to treat HBV and HCV infected individuals.References:Ganem D and Prince AM (2004) N Engl J Med, 350, 1118-1129.Te HS and Jensen DM (2010) Clin Liver Dis, 14, 1-21, vii.