Ph.D., 1992, Bombay University B.Sc., 1980, Bombay University
1. Molecular Modulators of HCV-Replication and Pathogenesis
Liver cancer caused by Hepatitis C virus (HCV) infection has become a major burden on the present health care system as patients with no symptoms eventually progress to varied clinical outcomes including acute hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The current combination therapy of interferon and ribavirin exhibits only 10-30 percent efficacy depending on the HCV genotype and suffers from the additional draw back associated with severe side effects. However, progress toward development of novel anti-HCV therapeutics has been hampered since a vast number of unanswered questions remain concerning HCV replication, progression, and pathogenesis.
Our long-range goal is to understand, at the molecular level, the role(s) of viral proteins, its RNA and host factors involved in HCV replication and pathogenesis and to facilitate the development of effective drugs/inhibitors against HCV. Our laboratory has expressed a functionally active recombinant HCV RNA polymerase (NS5B) which is capable of replicating HCV RNA in vitro. We have established a number of its biochemical characteristics and our investigating its mechanistic parameters. Employing a structure-functional approach, we are carrying out mutational analysis of specific catalytically conserved as well as unique amino acid residues of NS5B in order to elucidate their role in HCV RNA replication. The relevance of specific NS5B mutations on viral RNA replication in vivo is being evaluated via the sub-genomic HCV replicon. We are also screening for novel NS5B-specific inhibitors via structure-activity optimization approach and expect to identify NS5B-specific lead compounds. Another aspect of our studies pertains to screening and identification of host-proteins involved in HCV-host interactions. Since HCV replicase (NS5B) and the viral RNA constitute important components and key players of replication, we are using them as tools in order to screen for host interacting partners. We are employing the state-of the art two-hybrid and proteomic approach to screen for host-proteins from liver cells lines (Huh-7 and Hep G2) and from normal donor and HCV?infected liver explants. Upon confirming the identity of the host-interacting partner, we propose to establish the functional relevance of this interaction. A critical understanding of NS5B, in perspective of its structure-function relationships and its combinatorial interaction with other proteins, will provide insights into the molecular effectors mediating Hepatitis C Virus replication and pathogenesis and will further facilitate the development of effective drugs/inhibitors against HCV induced liver damage and carcinoma.
2. HCV infection and Hepatocelluar carcinoma
Studies are in planning phase to investigate the role of hepatitis C virus genomic mutation in hepatocelular carcinoma.