Hepatitis C virus (HCV) often causes persistent infection in humans, which may lead to progressive liver disease. We hypothesize that disease progression from chronic HCV infection is attributed, at least in part, to the effect of HCV core protein on the expression of host cellular genes. Our long term goal is to understand the underlying mechanisms behind HCV mediated liver disease progression. We were among the first to identify many intriguing functions related to HCV core protein, which may significantly contribute to disease progression. However, there are critical gaps in our understanding of the key cellular targets and molecular mechanisms by which core protein exerts these functions alone or in context to other HCV proteins. HCV induces hepatocellular insulin resistance and hepatic fibrogenesis. Our focus in this grant application is to examine the underlying mechanisms of HCV induced insulin resistance and fibrogenesis as a follow up to our preliminary data provided with this application. The current research proposal includes complementary but independent aims to address our hypothesis.
Aim 1 will investigate the mechanism of IRS phosphorylation by HCV core protein, Aim 2 will investigate the functional correlates of HCV core protein induced metabolic regulators, and Aim 3 will evaluate the role of HCV core protein in hepatic fibrosis. Studies will also be performed using full-length cDNA, replicon or cell culture grown HCV to provide a molecular basis for HCV core protein functions in context to other HCV proteins. Knowledge on the molecular determinants involved in HCV mediated disease progression will open avenues for novel therapeutic approach.

Public Health Relevance

Hepatitis C virus (HCV) often causes persistent infection and progressive liver disease. We plan to understand the molecular determinants involved in HCV mediated liver disease progression, which will open avenues for novel therapeutic approach.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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Saint Louis University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Bose, Sandip K; Kim, Hangeun; Meyer, Keith et al. (2014) Forkhead box transcription factor regulation and lipid accumulation by hepatitis C virus. J Virol 88:4195-203
Kim, Hangeun; Ray, Ranjit (2014) Evasion of TNF-?-mediated apoptosis by hepatitis C virus. Methods Mol Biol 1155:125-32
Kim, Hangeun; Bose, Sandip K; Meyer, Keith et al. (2014) Hepatitis C virus impairs natural killer cell-mediated augmentation of complement synthesis. J Virol 88:2564-71
Mukherjee, Anupam; Shrivastava, Shubham; Bhanja Chowdhury, Joydip et al. (2014) Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J Virol 88:7929-40
Kim, Hangeun; Meyer, Keith; Di Bisceglie, Adrian M et al. (2014) Inhibition of c3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components. PLoS One 9:e101422
Bose, Sandip K; Ray, Ranjit (2013) Association of lipid droplet and hepatitis C virus proteins: insights for virus replication. J Lipid Res 54:871-2
Mazumdar, Budhaditya; Kim, Hangeun; Meyer, Keith et al. (2012) Hepatitis C virus proteins inhibit C3 complement production. J Virol 86:2221-8
Bose, Sandip K; Shrivastava, Shubham; Meyer, Keith et al. (2012) Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J Virol 86:6315-22
Banerjee, Arup; Mazumdar, Budhaditya; Meyer, Keith et al. (2011) Transcriptional repression of C4 complement by hepatitis C virus proteins. J Virol 85:4157-66
Ait-Goughoulte, Malika; Banerjee, Arup; Meyer, Keith et al. (2010) Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute-phase response. Hepatology 51:1505-13

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