Heme Oxygenase-1 Inhibition of Hepatitis C Replication

血红素加氧酶 1 抑制丙型肝炎复制

• 批准号: 7686494
• 负责人: WARREN N SCHMIDT
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686494
• 关键词: Alcohol abuse; Antioxidants; Antiviral Agents; Antiviral Therapy; Attenuated; Basic Science; Bilirubin; Biliverdine; Carbon Monoxide; Caring; Cells; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; Data; Defense Mechanisms; Development; Down-Regulation; Enzymes; Equilibrium; Foundations; Genotype; Goals; Healthcare; Heme; Hemin; Hemostatic function; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; In Vitro; Incidence; Individual; Inflammation; Injury; Interferon-alpha; Interferons; Iron; Knowledge; Laboratories; Length; Life Cycle Stages; Liver; Liver diseases; Maintenance; Mediator of activation protein; Metabolic; Modality; Morbidity - disease rate; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygenases; Patients; Peroxides; Pharmaceutical Preparations; Population; Porphyrias; Prevention; Primary carcinoma of the liver cells; Reaction; Recurrence; Relapse; Replicon; Reporting; Research; Research Support; Ribavirin; Role; Sampling; Staging; Stress; Superoxides; Testing; Therapeutic; Time; Transcriptional Regulation; United States; Veterans; Viral; Virus; Virus Diseases; Virus Replication; Work; base; chronic liver disease; cohort; effective therapy; established cell line; global health; heme oxygenase-1; in vivo; interest; interferon therapy; liver transplantation; mortality; novel; novel strategies; overexpression; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a global health problem, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Nearly 50% of infected patients do not respond to interferon therapy and it is crucial to develop additional therapeutic modalities. Hepatic injury is likely initiated by oxidants such as superoxide and peroxide that arise during viral infection and damage hepatocytes and surrounding cells. Hepatocytes normally up- regulate oxidative defense enzymes to maintain redox balance and prevent liver injury. Heme oxygenase-1 (HO-1) is an oxidative defense enzyme that is induced in response to oxidative stress. The enzyme's reaction products, biliverdin, carbon monoxide, and iron serve important functions in the cell to maintain cellular hemostasis and prevent injury. Past work from our laboratory has shown that HCV can transcriptionally regulate expression of HO-1. More recently, we reported that HO-1 overexpression or induction with hemin can attenuate viral replication and at the same time protect against oxidative injury in HCV replicon cells. Consequently, our findings strongly suggest that induction of HO-1 with drugs such as hemin may be a new exciting avenue for adjunctive antiviral therapy to treat HCV infection and/or prevent chronic liver disease. The major objective of this application is to characterize the cellular mechanisms whereby HO-1 induction and its enzymatic products inhibit HCV replication and reduce oxidative stress. The central hypothesis of this application is that HO-1 is an important hepatocellular defense enzyme whose reaction products attenuate HCV replication as well as protect against oxidative injury caused by the virus. Using established cell lines of HCV nonstructural and full length replicons as well as JFH6 line that supports the cellular life cycle of HCV in vitro, we will test the central hypothesis and accomplish the major objectives by undertaking experiments of three specific objectives: 1) We will investigate the role of HO reaction products iron and biliverdin/bilirubin as mediators of HO-1 antiviral activity in HCV infected hepatocytes. 2) We will investigate the role of heme oxygenase reaction products, biliverdin/bilirubin, carbon monoxide, and iron in reducing and/or modulating oxidative stress due to the virus, and 3) We will investigate the role of HCV as a regulator of HO-1 expression, under basal conditions and in response to stress. Since HO-1 is induced in response to oxidative stress it is important to clarify how the virus must modulate HO-1 expression. This work will expand our knowledge of viral replication and hepatic injury that occur during chronic HCV infection. It will also lay a foundation for development of a novel class of antiviral agents that potentially could be adjunctive therapy for chronic HCV infection. Potential Impact on Veterans healthcare: Veterans have higher incidence rates of chronic HCV infection and suffer increased morbidity and mortality than the population at large. The results of these studies are highly likely to positively impact veterans' care with new treatment modalities and management options. PUBLIC HEALTH RELEVANCE: Hepatitis C virus is a global health problem. This work will study how the virus causes human liver disease and how the human liver responds to the virus. The importance of this work is that it will be directly applicable to treatment of humans with hepatitis C virus infection.

描述（由申请人提供）： 丙型肝炎病毒（HCV）是一个全球性的健康问题，导致慢性肝炎、肝硬化和肝细胞癌。近 50% 的感染患者对干扰素治疗没有反应，因此开发额外的治疗方式至关重要。肝损伤可能是由病毒感染过程中产生的氧化剂（例如超氧化物和过氧化物）引发的，并损害肝细胞和周围细胞。肝细胞通常上调氧化防御酶以维持氧化还原平衡并防止肝损伤。血红素加氧酶-1 (HO-1) 是一种氧化防御酶，响应氧化应激而被诱导。该酶的反应产物胆绿素、一氧化碳和铁在细胞中发挥重要作用，维持细胞止血和防止损伤。我们实验室过去的工作表明HCV可以转录调节HO-1的表达。最近，我们报道 HO-1 过表达或用氯高铁血红素诱导可以减弱病毒复制，同时保护 HCV 复制子细胞免受氧化损伤。因此，我们的研究结果强烈表明，用血红素等药物诱导 HO-1 可能是辅助抗病毒治疗治疗 HCV 感染和/或预防慢性肝病的新途径。本申请的主要目的是表征 HO-1 诱导及其酶产物抑制 HCV 复制和减少氧化应激的细胞机制。本申请的中心假设是 HO-1 是一种重要的肝细胞防御酶，其反应产物可减弱 HCV 复制并防止病毒引起的氧化损伤。使用已建立的 HCV 非结构和全长复制子细胞系以及支持 HCV 体外细胞生命周期的 JFH6 细胞系，我们将测试中心假设并通过进行三个具体目标的实验来实现主要目标：1）我们将研究 HO 反应产物铁和胆绿素/胆红素作为 HCV 感染肝细胞中 HO-1 抗病毒活性介质的作用。 2) 我们将研究血红素加氧酶反应产物、胆绿素/胆红素、一氧化碳和铁在减少和/或调节病毒引起的氧化应激中的作用，以及 3) 我们将研究 HCV 作为 H2O 调节剂的作用-1 表达，在基础条件下和对应激的反应。由于 HO-1 是响应氧化应激而诱导的，因此阐明病毒如何调节 HO-1 表达非常重要。这项工作将扩大我们对慢性 HCV 感染期间发生的病毒复制和肝损伤的了解。它还将为开发一类新型抗病毒药物奠定基础，该药物可能成为慢性丙型肝炎病毒感染的辅助治疗。对退伍军人医疗保健的潜在影响：退伍军人的慢性丙型肝炎感染发病率较高，发病率和死亡率高于一般人群。这些研究的结果很可能通过新的治疗方式和管理方案对退伍军人的护理产生积极影响。 公共卫生相关性： 丙型肝炎病毒是一个全球性的健康问题。这项工作将研究该病毒如何引起人类肝脏疾病以及人类肝脏如何对该病毒做出反应。这项工作的重要性在于它将直接应用于治疗丙型肝炎病毒感染的人类。