Heme Oxygenase-1 and Hepatitis C

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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.