Heme Oxygenase-1 and Hepatitis C

血红素加氧酶 1 和丙型肝炎

• 批准号: 6921206
• 负责人: WARREN N SCHMIDT
• 金额: $ 18.82万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921206
• 关键词: cellular respiration; clinical research; cytoprotection; cytotoxicity; enzyme activity; enzyme induction /repression; heme oxygenase; hepatitis C; hepatitis C virus; human subject; isozymes; liver cells; oxidative stress; replicon; virus protein

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a global health problem, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma, 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 injury. An important antioxidative enzyme is heme oxygenase-1 (HO-1) that is induced in response to oxidative stress in humans and animal models. Although the role of HO-1 in human liver disease has not been well-studied, available evidence suggests that the enzyme is usually up-regulated in response to injury. In contrast, recent data by our group have shown that HO-1 expression is down-regulated in HCV infected liver samples and that the HCV core protein transcriptionally down-regulates the enzyme in vitro. Collectively, these data suggest that suppression of HO-1 expression by HCV may contribute to hepatic injury. Our overall objective is to determine the role and importance of HO-1 in HCV liver disease and the pathologic consequences that result when the enzyme is down regulated by HCV. Our central hypothesis is that HO-1 is an important hepatocellular defense enzyme that overall prevents hepatocyte injury. Hepatitis C virus transcriptionally down regulates expression of HO-1 during chronic infection, which alters the susceptibility and response of the hepatocyte to injury. Using a large human liver sample bank for the in vivo studies and a variety of HCV protein and full length viral constructs in vitro, we will test the central hypothesis and accomplish the major objective by undertaking experiments of three specific aims: 1) We will test the hypothesis that down regulation of HO-1 in HCV liver disease is significantly related to, and important for hepatocyte injury in vivo. 2) We will test the hypothesis that HO-1 is transcriptionally down-regulated in contrast to HO-2 in Huh-7.5 hepatocytes expressing FL HCV replicons. 3) We will test the hypothesis that hepatocytes expressing FL HCV replicons are more sensitive to cellular injury and oxidative stress. We also hypothesize that over-expression of HO-1 will at least partially reverse the untoward effects of FL HCV replication and expression on cellular oxidative redox balance. These experiments will increase our understanding of the importance of HO-1 in HCV and other liver diseases and the putative injurious consequences that result when the enzyme is down-regulated. Further study of the regulation of HO-1 expression by HCV will lay the foundation for-improved therapeutic options1 for patients with chronic HCV disease such as targeted antioxidant gene therapy and selective antioxidants.

描述（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，病毒感染过程中产生超氧化物和过氧化物，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损伤。血红素加氧酶-1 (HO-1) 是一种重要的抗氧化酶，它是在人类和动物模型中响应氧化应激而诱导的。尽管 HO-1 在人类肝脏疾病中的作用尚未得到充分研究，但现有证据表明，该酶通常会因损伤而上调。相比之下，我们小组最近的数据表明，HCV 感染的肝脏样本中 HO-1 表达下调，并且 HCV 核心蛋白在体外转录下调该酶。总的来说，这些数据表明 HCV 抑制 HO-1 表达可能导致肝损伤。我们的总体目标是确定 HO-1 在 HCV 肝病中的作用和重要性，以及当 HCV 下调该酶时产生的病理后果。我们的中心假设是 HO-1 是一种重要的肝细胞防御酶，可总体防止肝细胞损伤。丙型肝炎病毒在慢性感染过程中转录下调 HO-1 的表达，从而改变肝细胞对损伤的敏感性和反应。使用大型人类肝脏样本库进行体内研究以及各种 HCV 蛋白和体外全长病毒构建体，我们将测试中心假设并通过进行三个特定目标的实验来实现主要目标：1）我们将测试HCV 肝病中 HO-1 的下调与体内肝细胞损伤显着相关且对其很重要的假设。 2) 我们将测试以下假设：在表达 FL HCV 复制子的 Huh-7.5 肝细胞中，与 HO-2 相比，HO-1 转录下调。 3) 我们将检验表达 FL HCV 复制子的肝细胞对细胞损伤和氧化应激更敏感的假设。我们还假设 HO-1 的过度表达将至少部分逆转 FL HCV 复制和表达对细胞氧化还原平衡的不良影响。这些实验将加深我们对 HO-1 在 HCV 和其他肝脏疾病中的重要性以及当该酶下调时可能产生的有害后果的理解。进一步研究 HCV 对 HO-1 表达的调节将为改善慢性 HCV 疾病患者的治疗方案（例如靶向抗氧化基因治疗和选择性抗氧化剂）奠定基础。