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

• 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
• 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

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.

慢性乙肝病毒感染仍然是一个主要的全球健康问题，尽管 有效的乙肝疫苗，影响到全球2.4亿人和125万美国人。乙肝病毒 是慢性肝炎、肝硬变和肝细胞癌等肝病的主要原因 癌症(HCC)。预防性乙肝疫苗对预防新的乙肝病毒感染是有效的，但 不能为已经感染了乙肝病毒的数亿人提供治疗益处。当前 含有干扰素和核苷类似物的抗病毒药物不能治愈乙肝。 世界卫生组织呼吁消除病毒性肝炎作为一种公共卫生 到2030年的威胁。治愈乙肝的最大挑战是如何共价清除乙肝病毒 闭合环状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的更有效的抗病毒药物 用于治疗乙肝。缺乏健壮的细胞培养和乙肝病毒繁殖的小动物模型 是治疗乙肝的主要障碍。最近，我们研制出了一种强大的 乙肝病毒细胞培养体系。更重要的是，我们发现人类载脂蛋白E (APOE)富含在乙肝病毒的包膜上，促进乙肝病毒的感染和产生。我们的 初步研究还发现，低密度脂蛋白受体(LDLR)和几个核心 硫酸乙酰肝素蛋白多糖(HSPGs)蛋白在乙肝病毒感染中起重要作用。我们 假设LDLR家族蛋白和HSPG作为细胞表面受体促进 乙肝病毒感染。我们的总体目标是确定其作用和潜在的分子机制 在体内外研究了低密度脂蛋白受体家族蛋白和热休克蛋白在乙肝病毒感染中的作用。这一目标将是 有三个具体目标：1)确定其重要性和分子机制 2)明确HSPGs在乙型肝炎病毒感染中的作用和分子基础。 3)确定低密度脂蛋白受体在体内乙肝病毒感染中的生理意义。 采用人源化小鼠和一种新的转基因乙肝小鼠模型。圆满完成 这一应用将填补关于新的乙肝病毒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乙肝病毒小鼠模型 朝着治愈慢性乙肝的方向迈进