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The focus of my research group is on the study of mammalian viruses that are significant causes of morbidity and mortality in humans, in particular hepatitis B virus (HBV), hepatitis C virus (HCV), and dengue virus (DENV). I have been especially interested in the development of a variety of chemical tools to characterize novel interactions between viral pathogens and their hosts at both the molecular and pathway levels.
First, I have led successful efforts in developing and using immunofluorescence image-based screens to identify both small molecules and shRNAs that perturb dengue virus replication. As we follow-up on our original kinase inhibitor screens, a significant portion of my group is currently focused on the characterization of the mechanisms by which Src, Abl, and other specific kinases regulate the dengue virus replication cycle.
Second, my group has developed small molecule inhibitors of dengue virus entry and used these as mechanistic probes in cellular and biochemical studies of the dengue virus entry. We have discovered inhibitors that can simultaneously inhibit two different steps of the dengue virus replication cycle through interactions with two distinct targets, one a host kinase and the other the envelope protein coating the virion surface.
Third, my group has developed global liquid chromatography - mass spectrometry based profiling as a way to identify host lipids and lipid metabolic pathways that are important for the replication of viral pathogens. In our initial work, we have focused on profiling HBV and HCV, two phylogenetically unrelated viruses that cause chronic infections in the liver. This work has led to the identification of virus-specific perturbations in sterol metabolism that promote viral replication. My group is actively investigating the mechanisms responsible for these perturbations as well as their biological significance in the viral life cycle and pathogenesis. In addition, we are performing comparative lipid metabolite profiling of additional viral pathogens to identify common pathways utilized by viruses that cause chronic versus acute infections and viruses that infect the liver versus those that infect other cells and tissues.
The members of my group come from diverse backgrounds including chemistry, biochemistry, cell biology, and virology. My group has the chemical and virological expertise as well as the instrumentation, collaborations, and institutional support to use these tools to study the basic virology and pathogenesis of these human viral pathogens. Our work with hepatitis B and C viruses as well as our work using small molecules to interrogate the signal transduction pathways of host protein kinases are geared towards understanding the role of viral pathogens in cancer biology.
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