Steven A. Weinman, M.D., Ph.D.
Professor
- Affiliations:
John Sealy Distinguished Chair for MD-PhD Studies
Professor of Internal Medicine
Professor of Neuroscience & Cell Biology
- Route: 0620 4.212E Research Building 17
- Tel: (409) 772-4286
- Fax: (409) 747-2187
- sweinman@utmb.edu
- Weinman Lab Webpage
Steven A. Weinman, M.D., Ph.D.
Education
•
M.D., Ph.D., 1984, Washington University
• Postdoctoral, Digestive Diseases, Yale University
Honors
• American Digestive Health Foundation Basic Science Research Award
• American Gastroenterological Association Research Scholar
Cellular Pathogenesis of Hepatitis C
Hepatitis C virus causes a chronic infection in humans that affects almost 2% of the world’s population. It is a member of the flavirus family that replicates in hepatocytes and triggers a number of host responses that lead to progressive liver injury and cancer. The focus of our lab is on the mechanisms by which the Hepatitis C virus interacts with mitochondria and how these viral-mitochondrial interactions contribute to the development of hepatocellular injury, cirrhosis and hepatocellular carcinoma. We are particularly interested in how viral-induced mitochondrial changes sensitize the liver to injury from environmental stresses such as alcohol consumption and drug toxicity. Prior research in our lab has discovered that the HCV core protein binds to mitochondria and increases the mitochondrial production of reactive oxygen species. This sets up a chain of events producing impaired mitochondrial electron transport and an altered cellular redox state. The resulting effects on signaling and cellular energy metabolism promote viral persistence and chronic liver injury. Current projects are examining the mechanisms by which viral proteins alter mitochondrial Ca2+ transport, exploring the role of HCV mitochondrial interactions in modulating cellular innate immunity, and determining the role of viral- and alcohol-induced redox events in promoting viral replication. We are also evaluating potential antioxidant therapies in both cellular and animal models of liver injury.
A second area of interest in the lab is how regulation of luminal pH in endocytic and secretory vesicles plays a role in the life cycle of HCV. Our lab has determined that a specific class of intracellular chloride transport proteins (the ClC family) is required for acidification and expansion of vesicles in hepatocytes. Intravesicular pH control is critical to the lifecycle of Hepatitis C virus and an HCV protein, p7, has been suggested to function as a proton channel, specifically required for assembly of viral particles. Ongoing studies are determining how ClC channels and the viral p7 protein regulate the events necessary for viral entry, fusion, and infectious particle formation. The goal of these studies is to understand how the elements of the cellular pH regulatory system can be targets for antiviral drug development. We collaborate actively with investigators in the UTMB Center for Hepatitis Research.
Selected Recent Publications
Osna, N.A., White, R.L., Krutik, V.M, Wang, T., Weinman, S.A., Donohue, T.M.. Proteasome activation by hepatitis C core protein is reversed by ethanol-induced oxidative stress. Gastroenterology 134:2144-2152, 2008
Li, Y., Boehning, D.F., Qian, T., Popov, V.L., Weinman, S.A., Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB Journal, 21:2474-85, 2007
Chen, Z., Benureau, Y., Rijnbrand, R., Yi, J., Wang, T., Warter, L., Lanford, R.E., Weinman, S.A., Lemon, S.M., Martin, A., Li, K. GB virus B disrupts RIG-I signaling by NS3/4A-meditated cleavage of the adaptor protein MAVS. J. Virol, 81:964-976, 2007
Zhao, Z., Li, X., Hao, J., Winston, J., Weinman, S.A. The CIC-3 chloride transport protein traffics through the plasma membrane via interaction of an N-terminal dileucine cluster with clathrin. J. Biol. Chem, 282:29022-29031, 2007
Wang, T., Weinman, S.A., Causes and consequences of mitochondrial reactive oxygen species generation in Hepatitis C. J Gastroenterol Hepatol, 3:S34-7, 2006.
Loo, YM., Owen, DM., Li, K., Erickson, AK., Johnson, CL., Fish, CL., Carney, DS., Wang, T., Ishida, H., Yoneyama, M., Fujita, T., Satio, T., Lee, WM., Hagedorn, CH., Lau, DT., Weinman, SA., Lemon, SM., Gale, M, Jr.Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA, 103:6001-6006, 2006.
Korenaga, M., Wang, T., Li, Y., Showalter, L., Chan, T., Sun, J., Weinman, S.A. Hepatitis C Virus Core Protein inhibits mitochondrial electron transport and increases ROS production. J.Biol Chem, 280:45-37841, 2005.
Otani, K., Korenaga, M., Beard, M.R., Li, K., Qian, T., Showalter, L.A., Singh, A.W., Wang, T., Weinman, S.A. Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology, 128:96-117, 2005.
Wang, T.; Weinman, S.A. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes formation of holoceruloplasmin. Gastroenterology. 126:1157-1168, 2004.