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Tyler Lab

Research Interests


 

Research Interests

Our laboratory uses reovirus infection of mice as an experimental model system to understand how viral pathogens interact with the host to produce disease and cellular injury. A major focus of our laboratory has been in the area of virus-induced apoptosis. We have shown that reoviruses can induce apoptosis both in vitro and in vivo, and that reovirus strains can differ in this capacity. Studies currently underway specifically focus on virus induced neuronal cell death and tissue injury in the brain and spinal cord which lead to neurologic disease. In addition to using the reovirus model we will also expand our studies to include additional mouse models of important human neurologic diseases, including West Nile virus (WNV) and herpes simplex virus (HSV) encephalitis. 

  1. Signal transduction in reovirus-induced apoptosis.
    • Reovirus-induced regulation of the transcription factor nuclear factor kappa B (NF-κB) is required for the apoptotic cell death of virus-infected cells and for neurologic disease. Reovirus-induced apoptosis requires both an early phase of activation and a later phase where the activation of NF-κB is blocked. We are currently interested in identifying specific NF-κB dependent genes that contribute to virus-induced neuronal death and tissue injury.
    • Activation of both c-Jun N-terminal kinase (JNK) and that c-Jun transcription factor are also associated with reovirus-induced cell death and neurologic disease. We are currently interested in identifying specific c-Jun dependent genes and JNK-dependent mechanisms that contribute to virus-induced neuronal death and tissue injury.
    • Reovirus-induced apoptosis is mediated by death receptors. In neurons soluble Fas inhibits reovirus-induced apoptosis suggesting that the binding of FasL to Fas is an important factor in virus-induced neuronal death. Fas is also up-regulated in the brain following reovirus infection. Reovirus can also sensitize cells, including cell lines derived from a variety of human cancers, to death receptor mediated apoptosis by a mechanism that involves an increase in the activation of caspase 8.
    • Mitochondrial apoptotic signaling is also activated in the brain following reovirus infection resulting in the activation of caspase 9. Mitochondrial apoptotic signaling may be triggered in the brain by the caspase 8-dependent cleavage of the Bcl-2 family protein Bid. We are currently determining the role of other Bcl-2 family proteins, including pro-apoptotic Bax, in reovirus-induced neuronal apoptosis. Additional studies will define the role of other components of mitochondrial apoptotic signaling in virus infected neurons, including the release of pro-apoptotic mitochondrial factors (such as smac/DIABLO) and cellular inhibitor of apoptosis proteins (IAPS).
    • The signaling molecule DAXX may provide a critical link between death receptor and JNK signaling in the brain. We have recently shown that DAXX is up-regulated in the brain following reovirus infection. Studies to determine the role of DAXX in virus-induced neuronal cell death are currently underway.
    • IFN signaling is activated in the brain following reovirus infection. Experiments in STAT-/- mice have demonstrated that the IFN response is protective and limits viral replication. Current studies will identify the role of specific IFN regulated proteins during viral encephalitis.
    • Reovirus infection of the brain activates transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling. Inhibition of these pathways reduces reovirus-induced neuronal apoptosis suggesting that they normally function as part of the host’s protective innate immune response against CNS viral infection.
  2. Virus-induced gene expression in animal models of neurologic disease. We have recently performed microarray analysis to determine virus-induced gene expression in the brain during reovirus encephalitis. We now propose to extend these studies by performing similar experiments using established mouse models of important human neurologic diseases, including WNV and HSV encephalitis. We hypothesize that genes that are differentially regulated in the brain following infection with all three encephalitic viruses will provide broad spectrum therapeutic targets for encephalitis induced by both known and unknown (emerging) viral pathogens.
  3. Development of new model systems for investigation of virus-induced neurologic disease. Reovirus infection of the mouse CNS provides a classic experimental system that has been used extensively to study viral pathogenesis. We have recently shown that reovirus infection of mice can also be used as a model for acute flaccid paralysis and spinal motor neuron death. In addition, we are currently developing the use of ex vivo coronal slices for our studies. Coronal slices are more appropriate for our experiments than primary neurons because virus-induced gene expression in the infected brain will likely be dependent on multiple cell types (neurons, glia, microglial, etc.) integrated into an intact neuronal network of synapses and supporting cells.  Coronal slice cultures will enable us to test therapeutic approaches in intact neuronal tissue without initially worrying about limitations imposed by pharmacologic delivery in vivo or blood-brain-barrier permeability.
  4. Flavivirus infections. We have recently begun to investigate flavivirus infections in the CNS using models of WNV infection in mouse primary neuronal cultures, ex vivo organotypic slice cultures, and in the intact mouse brain in vivo. Current projects in the laboratory include understanding the role of the TGFβ superfamily of signaling proteins in WNV encephalitis.  We also study the interaction of specific viral proteins with neuronal signaling complexes both in the neuronal cell body and in synaptic terminals. 
  5. Translational research and clinical trials aimed at finding new therapies for CNS infections.  In affiliation with University of Colorado Hospital, we are studying novel treatments for West Nile virus and Progressive Multifocal leukoencephalopathy.