Delineating differential cellular stress signaling responses induced by reovirus

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Mammalian cells are complex entities consisting of tens of thousands of genes. These genes are expressed at different times and to different extents to produce the hundreds of thousands to millions of different cell proteins that coordinate all cellular activities involved in development, homeostasis, repair and immunity. This coordination is regulated by cell signaling pathways. Viruses use and disrupt cell signaling pathways. Viruses also are much simpler than cells, being composed of only a few genes and proteins. Thus, viruses continue to serve as superb models for understanding fundamental aspects of cell biology, including signaling pathways. My long-term goals are to delineate these signaling processes; to determine how a non-pathogenic mammalian reovirus (MRV) affects cellular signaling, how cell signaling perturbations enhance or disrupt viral processes, to determine which viral genes induce these signaling responses, to determine if, and which, post-translational modifications promote or abrogate signaling, and to precisely elucidate what molecular regions and domains of specific viral proteins are responsible for these signaling processes. These studies will improve our understanding of basic cell biology and of a critically important master regulator of cellular processes. My lab group previously published mass spectrometry-based analyses of MRV-infected cells and showed that the two most common MRV serotypes (type 1 Lang, T1L and type 3 Dearing, T3D) induced differential cellular protein responses. We also have preliminary quantitative aptamer-based results showing similar differential responses in cell signaling pathways. My group will continue its programmatic study of how MRV affect cellular signaling. Our short-term goals are to confirm and extend the preliminary aptamer studies to identify cell proteins that are significantly dysregulated, screen these significant proteins by RNA interference to knock down the corresponding genes to determine their effects upon virus and cellular functions, and exploit a novel genetic characteristic of MRV to map which regions of which viral proteins induce these signaling perturbations. Collectively, these studies will allow us to delineate important molecular components of fundamental cellular processes. The HQP who are trained in my laboratory have, and will continue, to benefit from our expertise in molecular biology and proteomics, and will acquire in-demand skill sets that will be broadly applicable in a wide variety of biologically important systems. These new HQP will be well equipped for careers in basic scientific research focused on biochemistry, biotechnology, genetics, molecular biology, and proteomics.