Only a minority of HCV-infected individuals have progressive forms of chronic hepatitis that will result in cirrhosis in 20 to 30 years. This project is concerned with the biological basis of disease progression in chronic hepatitis C. We have noted that, to date, viral factors and the systemic immune response to HCV are poorly correlated with disease progression. The key pathobiological process that determines progression of liver disease in chronic hepatitis C is fibrogenesis, with hepatocyte cell death and proliferation playing lesser roles. In the present proposal, these processes are conceptualized as responses to hepatic inflammation and oxidative stress causing activation of hepatic stellate cells and liver cell injury. Thus our overall objective is to characterize how interactions between HCV, the hepatic inflammatory response and liver cells promote fibrogenesis and disease progression in chronic hepatitis C. In particular, we will test the hypothesis that, in the early stages of chronic HCV infection, an intrahepatic """"""""molecular map"""""""" can be created to identify subsets of individuals who will develop progression of liver disease. We will then seek to identify patterns of hepatic gene expression that correlate with the pathogenesis of fibrosis, hepatocyte death and proliferation. A particular focus will be on the identification of genes not previously known to be associated with individual susceptibility to HCV. A unique feature of these studies is that they will be performed on serial liver biopsy samples obtained at 3 to 5 year intervals from 200 patients with mild to moderate chronic hepatitis C who will be followed prospectively and monitored by quantitative liver functional assessments.
The Specific Aims are: 1) To establish the relationship between cytokine mediators of the hepatic inflammatory response, macrophage activation and the presence of oxidative stress in the liver, and to compare these with characteristics of the HCV infection in hepatocytes and other cell types; 2) To determine whether expression of these cytokines and/or oxidative stress correlate with the activity of hepatic fibrogenesis, using both cross-sectional and prospective longitudinal approaches. 3) To identify hepatic genes previously not known to be associated with a progressive course for hepatitis C. The findings may allow those individuals most at risk of progressive liver disease from HCV to be identified at a time when they are most likely to respond to antiviral therapy. It will also allow the design of adjunctive treatments more appropriately targeted towards the key pathogenic processes that determine disease progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056402-04
Application #
6524426
Study Section
Special Emphasis Panel (ZDK1-GRB-5 (M1))
Program Officer
Doo, Edward
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$132,100
Indirect Cost
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
Poustchi, Hossein; Negro, Francesco; Hui, Jason et al. (2008) Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol 48:28-34
Huang, Xiao X; McCaughan, Geoffrey W; Shackel, Nicholas A et al. (2007) Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosis. Liver Int 27:960-8
Bugianesi, Elisabetta; Marchesini, Gulio; Gentilcore, Elena et al. (2006) Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: Role of insulin resistance and hepatic steatosis. Hepatology 44:1648-55
Bandara, Priyanka; George, Jacob; McCaughan, Geoffrey et al. (2005) Antioxidant levels in peripheral blood, disease activity and fibrotic stage in chronic hepatitis C. Liver Int 25:518-26
Kumar, Dinesh; Farrell, Geoffrey C; Kench, James et al. (2005) Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C. J Gastroenterol Hepatol 20:1395-400
Sud, Archana; Hui, Jason M; Farrell, Geoffrey C et al. (2004) Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology 39:1239-47
Coverdale, Shirley A; Khan, Mahbub H; Byth, Karen et al. (2004) Effects of interferon treatment response on liver complications of chronic hepatitis C: 9-year follow-up study. Am J Gastroenterol 99:636-44
Hui, Jason M; Kench, James G; Chitturi, Shivakumar et al. (2003) Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 38:420-7
Hui, Jason M; Sud, Archana; Farrell, Geoffrey C et al. (2003) Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 125:1695-704
Seth, Devanshi; Leo, Maria A; McGuinness, Peter H et al. (2003) Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver. Am J Pathol 163:2303-17

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