EXCEED THE SPACE PROVIDED. Hepatitis C virus (HCV) is one of the leading causative agent of chronic hepatitis and cirrhosis. HCV infection of liver is associated with the development of hepatocellular carcinoma. It is estimated that about 4 million people in the US are infected with HCV. The RNA genome of this virus encodes a polyprotein of 3010 amino acids. HCV RNA genome consists of unique sequences and structures at its 5' and 3' termini, which are essential features required for viral translation and replication. The RNA genome codes for three structural proteins and at least six nonstructural proteins. One of the nonstructural proteins, NS5A has generated significant levels of interest due largely to its suggested role in interferon-resistance. In this application, we propose to investigate the functions assocaited with the HCV NS5A. Translation and replication functions of the HCV RNA genome are associated with the ER membrane. These activities in the ER induce ER stress and ER overload responses. ER stress leads to unfolded protein response (UPR) which leads to activation of whole host of ER chperone proteins. The ER overload resposne appears to involve two second messengers, calcium and reactive oxygen species. Their activities ultimately lead to the activation and translocation of transcription factors to the nucleus whereupon they bind cognate DNA sequences and regulated gene expression. NF-kB and STAT-3 are two such transcription factors which are activated by phosphorylation and are transported to nucleus. Herein, we propose to investigate the mechanism of activation of ER-nucleus signal transduction pathway by the HCV NS5A. These studies have the potential to provide information of direct relevance to the chronic liver disease pathogenesis including its progression to hepatocellular carcinoma associated with the HCV infection. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK061566-04
Application #
7111582
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Doo, Edward
Project Start
2003-01-08
Project End
2007-12-31
Budget Start
2005-07-01
Budget End
2005-12-31
Support Year
4
Fiscal Year
2005
Total Cost
$117,185
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kim, Seong-Jun; Jang, Jae Young; Kim, Eun-Jung et al. (2017) Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation. Hepatology 66:758-771
Nasimuzzaman, Md; Waris, Gulam; Mikolon, David et al. (2007) Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor. J Virol 81:10249-57
Waris, Gulam; Felmlee, Daniel Jeffery; Negro, Francesco et al. (2007) Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol 81:8122-30
Domitrovich, Angela M; Felmlee, Daniel J; Siddiqui, Aleem (2005) Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion. J Biol Chem 280:39802-8
Waris, Gulam; Siddiqui, Aleem (2005) Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication. J Virol 79:9725-34
Tardif, Keith D; Waris, Gulam; Siddiqui, Aleem (2005) Hepatitis C virus, ER stress, and oxidative stress. Trends Microbiol 13:159-63
Waris, Gulam; Turkson, James; Hassanein, Tarek et al. (2005) Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication. J Virol 79:1569-80
Domitrovich, Angela M; Diebel, Kevin W; Ali, Naushad et al. (2005) Role of La autoantigen and polypyrimidine tract-binding protein in HCV replication. Virology 335:72-86
Tardif, Keith D; Mori, Kazutoshi; Kaufman, Randal J et al. (2004) Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. J Biol Chem 279:17158-64
Waris, Gulam; Sarker, Shameema; Siddiqui, Aleem (2004) Two-step affinity purification of the hepatitis C virus ribonucleoprotein complex. RNA 10:321-9

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