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The main research objective of the Min laboratory is to develop translational disease intervention strategies for emerging and re-emerging strains of human influenza viruses. To this end, we are taking chemical genomics and RNA interference (RNAi) approaches to understand the host-pathogen relationship in an effort to simultaneously identify new targets and potential therapeutic small molecule compounds. As influenza virus relies on host cell proteins and their associated pathways to complete its life cycle, identifying the host factors required for virus replication provides valuable new targets for antiviral agents. We have conducted a genome-wide RNAi screen in a human respiratory epithelial cell line infected influenza viruses to identify host genes important for influenza virus replication. From the RNAi screening numerous host genes were found to be critical for influenza replication or host resistance genes using three assay endpoints that included influenza nucleoprotein (NP) localization, viral genome replication, and infectious virus production. The key signaling pathways linked to these genes were identified and will be validated by reporter systems. The results showed that several genes functioned as apex genes in host cell pathway, and targeting these genes with re-purposed small molecule drugs will phenotype RNAi-based gene silencing and inhibition influenza virus replication. These novel druggable targets will suggest new influenza intervention strategies with new classes of antiviral drugs for chemoprophylaxis and treatment.
In parallel, we investigate the mechanisms of immunity and disease pathogenesis associated with influenza infection to better understand innate and adaptive immune responses that provide the foundation necessary to facilitate therapeutic agent development. Our research vision is to understand the dynamics of host response to virus infection that will provide new strategies for resolving disease through the development of treatments. We are determining the molecular mechanism of influenza viral proteins contribute to pathogenesis and overcome host defense by inhibiting crucial cellular functions. Our research has already identified promising new viral targets, subjected into high-throughput screens, and identified novel small molecules. In addition, our research on influenza A viruses includes the analysis of virulence and mammalian host adaptation of H5 and H7 avian influenza viruses, which have the potential for causing the next pandemic. This research will address both the function and mechanism of action of the novel small molecule antiviral agents in the context of viral and/or cellular protein interactions and its findings could advance the field of antiviral therapies against emerging and re-emerging influenza viruses causing significantly high mortality and morbidity in human.
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