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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：
10214611
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/10214611
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 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 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/antagonist 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B型肝炎病毒（HBV）感染仍然是一个主要的全球健康问题，尽管有效的HBV疫苗，影响全球2.4亿人和125万美国人。HBV 是导致肝脏疾病如慢性肝炎、肝硬化和肝细胞癌的主要原因。癌（HCC）。预防性乙肝疫苗可以有效预防新的乙肝病毒感染，但不能为数亿已经感染HBV的人提供治疗益处。电流由干扰素和核苷类似物组成的抗病毒药物不能治愈B型肝炎。世界卫生组织呼吁消除病毒性肝炎作为公共卫生 2030年的威胁。治疗B型肝炎的最大挑战是如何共价消除HBV 闭合环状DNA（cccDNA），其是持续病毒复制的分子基础。因此，在本发明中，迫切需要发现和开发新类型的更有效的抗病毒药物用于治疗B型肝炎。缺乏稳定的细胞培养和HBV繁殖的小动物模型是寻找治疗B型肝炎的主要障碍。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 载脂蛋白E（apoE）富集在HBV包膜上，并促进HBV感染和产生。我们初步研究还发现，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）蛋白对于HBV感染是重要的。我们假设LDLR家族蛋白和HSPG作为细胞表面受体促进 HBV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HSPGs在HBV感染中的作用。这一目标将是解决了三个具体目标：1）确定的重要性和分子机制， LDLR家族蛋白在HBV感染中的作用; 2）确定HSPGs在HBV感染中的作用和分子基础。 HBV感染;和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。圆满完成该应用将填补关于新的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点和转基因HBV小鼠模型慢性B型肝炎的治疗方法。