HBV replication and carcinogenesis

描述（由申请人提供）：B肝炎病毒（HBV）是一种嗜肝病毒，可引起严重的肝脏疾病，包括急性和慢性肝炎、肝硬化和肝细胞癌（HCC）。世界上有3.5亿至4亿人长期感染这种病毒，估计每年造成100万人死亡。在美国，慢性HBV携带者人口约为120万，在中国，携带者人口约为1亿。近年来，我们发现HBV可以通过诱导自噬来增强其DNA复制。我们还发现，在小鼠模型中，削弱自噬可以诱导肝癌发生的启动，但可以阻止肝癌发生的进展。这些研究表明自噬在HBV复制和癌变过程中起重要作用。我们建议的研究是继续这些新的发现，以进一步研究HBV与其宿主之间的相互作用。具体而言，我们将研究HBV诱导的自噬的分子机制。我们最近的研究表明，HBV X蛋白可以与III类磷脂酰肌醇-3-激酶（PI 3 KC 3）结合，以增强其酶活性。因此，我们将进一步确定HBx和PI 3 KC 3之间的相互作用如何诱导自噬。我们还将研究自噬如何增强HBV DNA复制。我们将确定自噬空泡是否作为HBV DNA复制的平台，以及自噬是否影响调节HBV DNA复制的细胞因子。最后，我们将确定自噬在HBV诱导的肝癌发生中的作用。我们将研究为什么损伤自噬促进肝癌发生的开始，但同时抑制其进展。我们的注意力将集中在自噬的存在和不存在下产生的肝肿瘤的表型差异，肿瘤抑制因子在肝癌发生中的作用，以及自噬对肝肿瘤起始干细胞的影响。我们的研究将为我们了解HBV与其宿主细胞之间的相互作用提供重要信息，并有助于更好地了解HBV复制和致癌作用。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). There are 350-400 million people in the world chronically infected by this virus, resulting in an estimated 1 million deaths every year. In the U.S., the chronic HBV carrier population is about 1.2 million and in China, the carrier population is about 100 million. Recently, we discovered that HBV could induce autophagy to enhance its DNA replication. We also found that impairing autophagy could induce the initiation but impede the progression of hepatocarcinogenesis in a mouse model. These previous studies of ours demonstrated an important role of autophagy in HBV replication and carcinogenesis. Our proposed research is to continue these novel findings to further study the interplay between HBV and its host. Specifically, we will study the molecular mechanism of HBV-induced autophagy. Our recent studies indicated that the HBV X protein could bind to the class III phosphatidylinositol-3-kinase (PI3KC3) to enhance its enzymatic activity. For that reason, we will further determine how this interaction between HBx and PI3KC3 induces autophagy. We will also investigate how autophagy enhances HBV DNA replication. We will determine whether autophagic vacuoles serve as the platform for HBV DNA replication and whether autophagy affects cellular factors that regulate HBV DNA replication. Finally, we will determine the role of autophagy in HBV-induced hepatocarcinogenesis. We will examine why impairing autophagy facilitates the initiation of hepatocarcinogenesis and yet in the mean time inhibits its progression. Our attention will be focused on the phenotypic difference of liver tumors produced in the absence and presence of autophagy, the role of tumor suppressors in hepatocarcinogenesis, and the effect of autophagy on hepatic tumor-initiating stem cells. Our proposed research will generate important information for us to understand the interaction between HBV and its host cell and lead to a better understanding of HBV replication and carcinogenesis.