My long-term career goals are to achieve academic and research excellence in the field of herpes simplex virus pathogenesis with a focus on regulation of the viral genome during latent and reactivated infections of sensor neurons. Realization of this long term goal will require the use of multiple experimental tools to integrate answers and observations made in vitro and in vivo. An understanding of this mechanism should lead to design of strategies to prevent HSV induced diseases. My short term goals will continue to be focused upon the role of the neuron in regulating the latent and reactivated HSV genome. The proposed research career award will be instrumental in achieving these goals by allowing me to focus the extensive time and energy required to carry out the research outlined in this proposal and to develop hypotheses and methods for future research related to the long term goal. The University of Missouri and the Department of Veterinary Pathobiology fully support this application and provide an excellent environment for the continued developed of my research career. The underlying basis of HSV induced diseases is latent viral infection of sensory neurons. This project will use transgenic technology to test whether host transcriptional proteins control latent HSV infection of neurons in vivo. The experiments described in this proposal are intended to begin to delineate the underlying mechanism by which HSV is regulated by host neurons during latent and reactivated infections.
The specific aims of this project are: 1) Establish whether host transcriptional proteins can regulate HSV IE genes in neurons in vivo and whether viral IE genes can be regulated in a way that would be appropriate for controlling latent and reactivated infections. 2) Determine whether inhibition of stimulation of viral IE gene expression will result in alteration of the ability of HSV to establish a latent infection and reactivate. 3) Determine whether host transcriptional regulatory proteins can modulate latent and reactivated HSV infections of sensory ganglia in transgenic mouse models.
|Loiacono, Christie M; Myers, Robert; Mitchell, William J (2004) The herpes simplex virus type 1 early gene (thymidine kinase) promoter is activated in neurons of brain, but not trigeminal ganglia, of transgenic mice in the absence of viral proteins. J Neurovirol 10:116-22|
|Loiacono, C M; Taus, N S; Mitchell, W J (2003) The herpes simplex virus type 1 ICP0 promoter is activated by viral reactivation stimuli in trigeminal ganglia neurons of transgenic mice. J Neurovirol 9:336-45|
|Loiacono, Christie M; Myers, Robert; Mitchell, William J (2002) Neurons differentially activate the herpes simplex virus type 1 immediate-early gene ICP0 and ICP27 promoters in transgenic mice. J Virol 76:2449-59|
|Taus, N S; Mitchell, W J (2001) The transgenic ICP4 promoter is activated in Schwann cells in trigeminal ganglia of mice latently infected with herpes simplex virus type 1. J Virol 75:10401-8|
|Galle, L E; Taus, N S; Maggs, D J et al. (2001) Increased severity of herpes simplex virus type 1-induced keratitis in Hox A5 transgenic mice. Curr Eye Res 23:435-42|
|Chang, E; Galle, L; Maggs, D et al. (2000) Pathogenesis of herpes simplex virus type 1-induced corneal inflammation in perforin-deficient mice. J Virol 74:11832-40|