In search of an HBV cure: novel model systems and targets

寻找乙型肝炎治愈方法：新的模型系统和目标

• 批准号: 10165482
• 负责人: Charles M Rice
• 金额: $ 59.43万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165482
• 关键词: Adenoviruses; Affect; Antiviral Response; Biological Models; Biology; Cell Nucleus; Cells; Chronic; Chronic Hepatitis B; Circular DNA; Clinical Trials; Collection; Data; Ectopic Expression; Foundations; Genes; Genome; Goals; Hepatitis B Virus; Hepatitis C virus; Hepatocyte; Human; In Vitro; Infection; Injectable; Integration Host Factors; Interferon-alpha; Interferons; Knock-out; Knowledge; Label; Lead; Liver; Liver Cirrhosis; Maps; Medical; Methods; Mus; Oral; Pathway interactions; Patients; Physiology; Primary carcinoma of the liver cells; Proteins; Recording of previous events; Risk; Role; Signal Pathway; System; TNF gene; Therapeutic Intervention; Toxic effect; Ubiquitin; Ubiquitination; Vaccines; Viral Genome; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Work; anti-hepatitis B; base; cytokine; drug development; druggable target; effective therapy; experience; genome-wide; hepatoma cell; high risk; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; loss of function; novel; nucleoside analog; pre-clinical; prevent; response; side effect; single-cell RNA sequencing; stem cells; success; tissue culture; transcription factor; transcriptome; transcriptome sequencing; ubiquitin-protein ligase; virus host interaction

Project Summary There are more than 250 million carriers of chronic hepatitis B virus (HBV) worldwide at risk of developing liver cirrhosis and hepatocellular carcinoma. To reduce this risk, two anti-HBV therapies are available: nucleoside analogs and interferon alpha (IFNα). Nucleoside analogs suppress viral replication but rarely lead to a cure due to the stability of the HBV genome as a covalently closed circular DNA (cccDNA). In contrast, IFNα cures approximately 10% of patients, but treatment has severe side effects and most patients don't benefit. Therefore, well-tolerated and more effective treatments are needed. Because IFNα can cure HBV, we sought to elucidate which interferon stimulated genes (ISGs) and pathways inhibit HBV. To this end, we screened a collection of ISGs and identified a potent HBV inhibitor. In addition, while conducting a genome-wide knockout screen for adenovirus, we identified a cellular protein that we later found was also necessary for HBV infection. Here we propose to characterize the mechanism of action of these two host factors and determine which cellular pathways affect HBV infection. Many aspects of the HBV lifecycle are not well understood due to the lack of robust in vitro and in vivo model systems. In recent years we have applied many of our liver systems and our expertise honed while studying hepatitis C virus to study hepatitis B virus. These efforts have laid the foundation for the proposed work and the model systems we will use while carrying out this work are a unique strength of the proposal. Overall, with our proposed work we will gain further insight into HBV biology and the host determinants of HBV infection. We hope this will uncover new strategies to cure chronic HBV infection.

项目摘要 全世界有超过2.5亿慢性B型肝炎病毒（HBV）携带者处于发展肝脏的风险中 肝硬化和肝细胞癌为了降低这种风险，有两种抗HBV疗法可用：核苷 类似物和干扰素α（IFNα）。核苷类似物抑制病毒复制，但很少导致治愈 由于HBV基因组作为共价闭合环状DNA（cccDNA）的稳定性。相比之下，IFNα治愈 大约10%的患者，但治疗有严重的副作用，大多数患者没有受益。 因此，需要耐受性良好且更有效的治疗。 由于IFNα可以治愈HBV，我们试图阐明哪些干扰素刺激基因（ISG）和 途径抑制HBV。为此，我们筛选了一系列ISG并鉴定了一种有效的HBV抑制剂。在 此外，在进行腺病毒全基因组敲除筛选时，我们鉴定了一种细胞蛋白， 我们后来发现也是HBV感染所必需的。在这里，我们建议描述 这两种宿主因子的作用，并确定哪些细胞途径影响HBV感染。 由于缺乏可靠的体外和体内研究，HBV生命周期的许多方面尚未得到很好的理解。 模型系统近年来，我们已经应用了许多肝脏系统和我们的专业知识， 从研究丙型肝炎病毒到研究B型肝炎病毒。这些努力为拟议的 工作和模型系统，我们将使用，同时进行这项工作是一个独特的优势的建议。 总的来说，通过我们的工作，我们将进一步了解HBV生物学和HBV的宿主决定因素 感染我们希望这将揭示治疗慢性HBV感染的新策略。