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：
10390437
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/10390437
关键词：
Address Affect American Animal Model 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 Crossbreeding DNA biosynthesis Development Drug Targeting Enzymes Gene Expression Genes Glypican Goals HBV Animal Model Hela Cells Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Hepatitis 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 Maintenance Mediating Modeling Molecular Monoclonal Antibodies Mus Na(+)-taurocholate-cotransporting peptide Patients Persons 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 hepatitis Virus Diseases Virus Receptors Virus Replication World Health Organization anti-hepatitis B antibody inhibitor apolipoprotein E receptor 2 apolipoprotein E-3 drug development 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

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.

慢性丙型肝炎病毒（HBV）感染仍然是全球主要的健康问题有效的HBV疫苗，全球影响2.4亿人和125万美国人。 HBV 是肝病，例如慢性肝炎，肝硬化和肝细胞的主要原因癌（HCC）。预防性HBV疫苗可有效预防新的HBV感染，但确实有效没有为已经感染HBV的数百万人提供治疗益处。当前的由干扰素和核苷类似物组成的抗病毒药物不是乙型肝炎的治愈性。世界卫生组织呼吁消除病毒肝炎作为公共卫生到2030年威胁。治愈乙型肝炎的最大挑战是如何协调消除HBV 闭合圆形DNA（CCCDNA），这是持续病毒复制的分子基础。因此，迫切需要发现和开发新的抗病毒药物的新类别用于治愈乙型肝炎。缺乏强大的细胞培养和HBV传播的小动物模型是寻找治疗乙型肝的主要障碍。最近，我们开发了一个强大的 HBV细胞培养系统。更重要的是，我们发现人载脂蛋白E （APOE）富含HBV包膜，并促进HBV感染和生产。我们的初步研究还发现，低密度脂蛋白受体（LDLR）和几个核心乙酰硫酸肝素蛋白聚糖（HSPG）的蛋白质对于HBV感染很重要。我们假设LDLR家族蛋白和HSPG是促进细胞表面受体 HBV感染。我们的总体目标是确定角色和潜在的分子机制在体外和体内HBV感染中的LDLR家族蛋白和HSPG中。这个目标将是由三个特定目的解决：1）确定的重要性和分子机制 HBV感染中的LDLR家族蛋白； 2）定义HSPG中HSPG的作用和分子基础 HBV感染； 3）确定LDLR在体内HBV感染中的生理重要性使用人性化小鼠和新的转基因HBV小鼠模型。成功完成该应用程序将填补有关新的HBV附件受体的知识差距，并提供新颖用于发现和开发新疗法的靶标和转基因HBV鼠标模型迈向治愈慢性肝炎。