HBV replication and carcinogenesis

乙型肝炎病毒复制和致癌作用

• 批准号: 8544645
• 负责人: J.-H. James Ou
• 金额: $ 20.01万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544645
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute Hepatitis; Affect; Age-Months; Attention; Autophagocytosis; Binding; Cell Culture Techniques; Cells; Cessation of life; China; Chronic Hepatitis; Chronic Hepatitis B; Complex; DNA biosynthesis; Genome; Goals; Grant; Hepatic; Hepatitis B Virus; Hepatitis B X-Protein; Hepatocarcinogenesis; Hepatocyte; Human; Hyperplasia; Infection; Knock-out; Knowledge; Lead; Length; Life Cycle Stages; Liver; Liver Cirrhosis; Liver diseases; Liver neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Mus; Patients; Play; Population; Primary carcinoma of the liver cells; Proteins; Research; Role; Stem cells; Time; Transgenic Mice; Tumor Suppressor Proteins; Vacuole; Virus; Virus Replication; adenoma; carcinogenesis; hepatoma cell; improved; inhibition of autophagy; liver transplantation; mouse model; novel; pathogen; public health relevance; tumor; viral DNA

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.

描述（申请人提供）：乙型肝炎病毒（HBV）是一种嗜肝病毒，可引起严重的肝脏疾病，包括急慢性肝炎、肝硬化和肝细胞癌（HCC）。全球有 3.50 至 4 亿人长期感染这种病毒，估计每年导致 100 万人死亡。在美国，慢性乙肝病毒携带者人数约为120万，在中国，慢性乙肝病毒携带者人数约为1亿。最近，我们发现HBV可以诱导自噬来增强其DNA复制。我们还发现，在小鼠模型中，损害自噬可以诱导肝癌的发生，但会阻碍肝癌发生的进展。我们之前的这些研究证明了自噬在 HBV 复制和致癌作用中的重要作用。我们提出的研究是继续这些新发现，进一步研究乙型肝炎病毒与其宿主之间的相互作用。具体来说，我们将研究HBV诱导自噬的分子机制。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（PI3KC3）结合以增强其酶活性。因此，我们将进一步确定 HBx 和 PI3KC3 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。我们将确定自噬液泡是否作为 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害自噬会促进肝癌的发生，但同时会抑制其进展。我们的注意力将集中在自噬不存在和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。我们提出的研究将为我们提供重要信息，帮助我们了解 HBV 与其宿主细胞之间的相互作用，并更好地了解 HBV 复制和致癌作用。