Cell surface receptors promoting hepatitis B virus infection

促进乙型肝炎病毒感染的细胞表面受体

基本信息

批准号：
10617179
负责人：
GUANGXIANG George LUO
金额：
$ 46.88万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617179
关键词：
Address Affect American Antiviral Agents Antiviral Therapy Apolipoprotein E Binding Biological Assay Blocking Antibodies CRISPR/Cas technology Cell Culture System Cell Culture Techniques Cell Line Cell Surface Receptors Cell-Matrix Junction Cessation of life Chronic Chronic Hepatitis Chronic Hepatitis B Circular DNA Cirrhosis Core Protein Cross Infection Crossbreeding DNA Maintenance DNA biosynthesis Development Drug Targeting Enzymes GPC3 gene Gene Expression Genes Glypican Goals HBV Animal Model Hela Cells Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Hepatitis B Hepatitis B Infection Hepatitis B Vaccines Hepatitis B Virus Hepatitis C Antiviral Hepatocyte Human In Vitro Infection Interferons Knock-in Mouse Knock-out Knockout Mice Knowledge Liver diseases Low Density Lipoprotein Receptor Mediating Modeling Molecular Monoclonal Antibodies Mus Na(+)-taurocholate-cotransporting peptide Patients Persons Pharmaceutical Preparations Physiological Play Primary carcinoma of the liver cells Production Proprotein Convertases Protein Family Public Health Risk Role Small Interfering RNA Subtilisins Surface Therapeutic Transgenic Mice Transgenic Organisms VLDL receptor Viral Viral hepatitis Virus Diseases Virus Receptors Virus Replication World Health Organization anti-hepatitis B apolipoprotein E receptor 2 apolipoprotein E-3 experimental study global health humanized mouse in vivo inhibitor knockout gene mouse model novel novel therapeutics nucleoside analog overexpression prevent prophylactic proteoglycan core protein receptor virus envelope virus identification

项目摘要

Chronic hepatitis B virus (HBV) infection remains a major global health problem despite of effective HBV vaccine, affecting 240 million people worldwide and 1.25 million Americans. HBV is a leading cause of liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Prophylactic HBV vaccine is effective to prevent new HBV infection but does not offer therapeutic benefit to the hundreds of million people already infected with HBV. Current antiviral drugs consisting of interferon and nucleoside analogues are not curative of hepatitis B. The World Health Organization has called for the elimination of viral hepatitis as a public health threat by 2030. The biggest challenge for a cure of hepatitis B is how to eliminate HBV covalently closed circular DNA (cccDNA), which is the molecular basis for persistent viral replication. Thus, there is an urgent need to discover and develop new classes of more efficacious antiviral drugs for curing hepatitis B. The lack of robust cell culture and small animal models of HBV propagation is a major barrier towards finding a cure for hepatitis B. Recently, we have developed a robust HBV cell culture system. More significantly, we have discovered that human apolipoprotein E (apoE) is enriched on the HBV envelope and promotes HBV infection and production. Our preliminary studies also found that the low-density lipoprotein receptor (LDLR) and several core proteins of heparan sulfate proteoglycans (HSPGs) are important for HBV infection. We hypothesize that the LDLR family proteins and HSPGs serve as cell surface receptors promoting HBV infection. Our overall goal is to determine the roles and underlying molecular mechanism of the LDLR family proteins and HSPGs in HBV infection in vitro and in vivo. This objective will be addressed by three specific aims: 1) to determine the importance and molecular mechanism of the LDLR family proteins in HBV infection; 2) to define the role and molecular basis of HSPGs in HBV infection; and 3) to determine the physiological importance of LDLR in HBV infection in vivo using humanized mice and a new transgenic HBV mouse model. The successful completion of this application will fill a knowledge gap about new HBV attachment receptors and provide novel targets and transgenic HBV mouse model for discovery and development of new therapeutics towards a cure of chronic hepatitis B.

尽管慢性乙型肝炎病毒（HBV）感染仍然是一个主要的全球健康问题有效的乙肝疫苗，影响了全球 2.4 亿人和 125 万美国人。乙型肝炎病毒是导致慢性肝炎、肝硬化和肝细胞性肝病等肝脏疾病的主要原因癌（HCC）。预防性乙型肝炎疫苗可有效预防新的乙型肝炎病毒感染，但无法为数亿已感染 HBV 的人提供治疗益处。当前的由干扰素和核苷类似物组成的抗病毒药物不能治愈乙型肝炎。世界卫生组织呼吁消除病毒性肝炎作为公共卫生问题到2030年将面临威胁。治愈乙型肝炎的最大挑战是如何共价消除乙型肝炎病毒闭环DNA（cccDNA），是病毒持续复制的分子基础。因此，迫切需要发现和开发新型更有效的抗病毒药物用于治疗乙型肝炎。缺乏乙型肝炎病毒传播的稳健细胞培养和小动物模型是寻找乙型肝炎治愈方法的主要障碍。最近，我们开发了一种强大的方法乙型肝炎病毒细胞培养系统。更重要的是，我们发现人类载脂蛋白E (apoE) 在 HBV 包膜上富集，促进 HBV 感染和产生。我们的初步研究还发现低密度脂蛋白受体（LDLR）和几个核心硫酸乙酰肝素蛋白聚糖 (HSPG) 的蛋白质对于 HBV 感染很重要。我们假设 LDLR 家族蛋白和 HSPG 作为细胞表面受体，促进乙型肝炎病毒感染。我们的总体目标是确定作用和潜在的分子机制 LDLR 家族蛋白和 HSPG 在体外和体内 HBV 感染中的作用。这一目标将是解决三个具体目标：1）确定重要性和分子机制 HBV 感染中的 LDLR 家族蛋白； 2）定义HSPG的作用和分子基础乙型肝炎病毒感染； 3) 确定LDLR在体内HBV感染中的生理重要性使用人源化小鼠和新的转基因 HBV 小鼠模型。顺利完成该应用将填补有关新 HBV 附着受体的知识空白，并提供新的用于发现和开发新疗法的靶标和转基因 HBV 小鼠模型致力于治愈慢性乙型肝炎。