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Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University

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Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 Molecular Mechanisms Involved Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis Ryan Fassnacht Virginia Commonwealth University Follow this and additional works at: http://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from http://scholarscompass.vcu.edu/etd/2246 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Ryan C. Fassnacht 2010 All Rights Reserved Molecular Mechanisms Involved in the Interaction Effects of HCV and Ethanol on Liver Cirrhosis A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Ryan Christopher Fassnacht, B.S. Hampden Sydney University, 2005 M.S. Virginia Commonwealth University, 2010 Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery Virginia Commonwealth University Richmond, Virginia July 9, 2010 Acknowledgement The Author wishes to thank his family and close friends for their support. He would also like to thank the members of the molecular transplant team for their help and advice. This project would not have been possible with out the help of Dr. Valeria Mas and her endearing patience. ii TABLE OF CONTENTS List of Tables………………………………………………………………………………v List of Figures…………………………………………………………………………….vi List of Abbreviations…………………………………………………………………….vii Abstract…………………………………………………………………………………...ix Introduction………………………………………………………………………………..1 What is the Hepatitis C Virus?.........................................................................................…2 Pathogenesis of Hepatitis C Virus Infection………………………………………4 Mechanisms of Hepatic Fibrosis…………………………………………………………..7 Oxidative Stress…………………………………………………………………...9 Immunomodulation………………………………………………………………11 Alcohol and HCV………………………………………………………………………..12 Hypothesis and Aims…………………………………………………………………….13 Patients Materials and Methods………………………………………………………….14 Patients and Samples……………………………………………………………..14 Sample Preparation………………………………………………………………15 Quality Assessment………………………………………………………………16 Microarray Data Analysis………………………………………………………..17 Gene Annotation…………………………………………………………………19 Verification of Microarray Data…………………………………………………20 Results……………………………………………………………………………………21 Analysis of Gene Expression patterns Between Alcoholic Cirrhotic Liver Tissue and Normal Liver Tissue………………………………………………..21 Differential Gene Expression between HCV Cirrhotic Liver Tissue and Normal Liver Tissue……………………………………………………………...23 iii Genes Involve in the Significant Interaction of HCV and Ethanol.………....………......24 Gene Expression Validation by QPCR…………………………………………..27 Discussion………………………………………………………………………………..37 List of References…………….………………………………………………………….43 Vita…………………………………………………………………………..….………241 iv List of Tables 1. Summary of More Important Findings in Each Analysis……………………………..33 S1. Genes Significantly Different Between ALD Cirrhotic Tissue Compared to Normal Liver Tissue ……………………………………………......................................50 S2. Genes Significantly Different Between HCV Cirrhotic Tissue compared to Normal Tissue…….………………………………………………..................................105 S3. Genes With Significant Estimate Value for the Interaction of HCV and Alcohol…….. …………………………………………………………………..………………………191 v List of Figures 1. Heat Map Generated From Unsupervised Cluster Analysis…………………………. 28 2. HCV Cirrhotic vs. Normal Tissue: Interferon Signaling.……………………………..29 3. Top Canonical Pathways Involved in the Interaction of HCV*EtOH………………...30 4. Significant Interaction (HCV*EtOH): Antigen Presentation Pathway………………..31 5. Toxicology Lists for the Interaction of HCV*EtOH………………………………….32 vi List of Abbreviations ADH.……………………………………………………………..Alcohol Dehydrogenase ALD….…………………………………………………………...Alcoholic Liver Disease APC……………………………………………………………….Antigen Presenting Cell C……………………………………………………………………...Core protein of HCV cDNA……………………………………………………………….Complementary DNA cRNA………………………………………………………………..Complementary RNA Ct…………………………………………………………………………...Cycle threshold CTL………………………………………………………………Cytotoxic T Lymphocyte CYP2E1…………………………………………………………….Cytochrome P450 2E1 DC.……..……………………………………………………………………Dendritic Cell dsRNA……………………………………………………………...Double Stranded RNA E………………………………………………………………....Envelope protein of HCV ECM………………………………………………………………….Extra-cellular Matrix ER…………………………………………………………………Endoplasmic Reticulum EtOH………………………………………………………………………………..Ethanol HBV……………………………………………………………………...Hepatitis B Virus HCC.……………………………………………………………Hepatocellular Carcinoma HCV……………………………………………………………………...Hepatitis C Virus HSC…………………………………………………………………...Hepatic Stellate Cell IFN.………………………………………………………………………………Interferon IPA…………………………………………………………....Ingenuity Pathway Analysis IRF…………………………………………………………...Interferon Regulatory Factor ISG…………………………………………………………….Interferon Stimulated Gene JAK…………………………………………………………………………..Janus Kinase vii KC.…………………………………………………………………………….Kupffer Cell MDA……………………………………………………………………..Malondialdehyde NF-κB.………………………………………………………….....Nuclear Factor-kappa B NS…………………………………………………………Non-Structural protein of HCV NK……………………………………………………………….……..Natural Killer Cell OLT……………………………………………………...Orthotopic Liver Transplantation PAMP…………………………………………….Pathogen Associated Molecular Pattern QPCR ……..Quantitative Reverse Transcriptase ‘Real Time’ Polymerase Chain Reaction RIG-1…………………………………………………….Retinoic-Acid-Inducible-Gene-1 RdRp.…………………………………………………..RNA-dependent RNA polymerase RMA………………………………………………………...Robust Multiarray Averaging rRNA……………………………………………………………………...Ribosomal RNA ROS……………………………………………………………...Reactive Oxygen Species S………………………………………………………………...Structural protein of HCV SOCS…………………………………………………...Suppressor of Cytokine Signaling ssRNA……………………………………………………………….single-stranded RNA STAT……...............................................Signal Transducer and Activator of Transcription Th……………………………………………………………………………...T helper cell TLR…………………………………………………………………….Toll-Like Receptor TRIF…………………...Toll/IL-1 Receptor-Domain-Containing Adaptor Inducing IFN-β TYK……………………………………………………………………….Tyrosine Kinase UNOS…………………………………………………..United Network of Organ Sharing viii ABSTRACT MOLECULAR MECHANISMS INVOVLED IN THE INTERACTION EFFECTS OF HCV AND ETHANOL IN LIVER CIRRHOSIS By Ryan C. Fassnacht, M.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University Virginia Commonwealth University, 2010 Thesis Director: Valeria Mas, Ph.D., Associate Professor of Surgery and Pathology Division of Transplant Department of Surgery The leading causes of liver disease are Hepatitis C virus infection and chronic alcohol abuse. Alcohol accelerates liver disease in HCV but the mechanisms are poorly understood. The identification of molecular gene expression profiles on human liver tissue was performed using microarrays. Samples were obtained from alcoholic-cirrhotic, HCV-cirrhotic, HCV/alcohol-cirrhotic and control non-cirrhotic liver tissue. Probe set expression summaries were calculated using RMA. Probe set level linear models were fit where probe set expression was modeled by HCV status, alcohol status, and the interaction between HCV and Alcohol. HCV cirrhosis was associated with up-regulation of genes related to viral and immune response, apoptosis and inflammation. There were down-regulation of genes in the ubiquititin-proteasome system in alcoholic cirrhosis. The interaction of HCV and alcohol revealed negative interaction for genes involved in apoptosis and immune response. There was a negative estimate for genes involved in class II restricted antigen presentation. Introduction Chronic Liver diseases of any etiology are the 9th leading cause of death in the United States (1). The leading causes of liver disease are Alcoholic Liver Disease (ALD) and chronic Hepatitis C Virus (HCV) infection, either alone or in combination, as they account for close to two- thirds of deaths from and patients with chronic liver diseases (1,2,3). The liver is vulnerable to sustained, chronic injury because the hepatocyte is the primary site of HCV replication as well as the metabolism of ethanol; thus it is intuitive that there is an interaction in the pathogenesis of HCV and alcohol (4). Despite clinical evidence of exacerbated injury, higher mortality rates and increased risk of hepatocellular carcinoma (HCC), liver disease mediated by the interaction of alcohol and HCV is complex and not completely understood. Pathogenesis of alcohol and HCV have similar effects of injury but arrive at those effects via different mechanisms as both etiologies manifest the four sequential hallmarks of liver disease: steatosis (fatty liver), steatohepatitis (inflamed fatty liver), fibrosis and HCC (5). 1 What is the Hepatitis C virus? Hepatitis C is a single stranded positive sense RNA virus (6) that was discovered in 1989. The virus is transmitted through bodily fluids, and most of those infected are intravenous drug users (7). Over 170 million people worldwide are infected with the virus (8). The progression of the virus is slow, most people are not aware of their infection until presented with a compromised liver; the onset
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