Viral infection of the central nervous system (CNS) is associated with a variety of neurologic diseases including meningitis, encephalitis, and myelitis, which have substantial morbidity and mortality and for which successful treatments are limited. The events that lead to virus-induced cell death, tissue injury and disease are not clearly understood. An increased understanding of the mechanisms by which neurotropic viruses kill cells in the CNS is thus a critical factor in the design of new therapeutic strategies. Apoptosis has been implicated as a mechanism of virus-induced CNS disease. In this proposal apoptotic signaling pathways and the regulation of these pathways will be investigated following viral infection of the CNS. Reovirus infection of neonatal mice and cultured neurons, which has proved to be one of the most important models for studying viral pathogenesis in the CNS, will be used for these studies. The role of virus-induced mitogen activated protein kinases (specific aim 1), transcription factors (specific aim 2) and gene expression changes (specific aim 3) will be investigated during death receptor and mitochondrial apoptotic signaling following reovirus infection of neuronal cells.
In specific aim 3 non-targeted (microarray analysis), in addition to targeted, approaches will be used in order to elucidate novel viral mechanisms of CNS pathogenesis. Taken together these studies are designed to identify the regulation of apoptotic signaling during virus-induced apoptosis of the CNS. They are expected to have direct therapeutic implications for the development of novel therapies for CNS disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050138-02
Application #
7000454
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Golanov, Eugene V
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$256,075
Indirect Cost
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Dionne, Kalen R; Tyler, Kenneth L (2013) Slice culture modeling of central nervous system (CNS) viral infection. Methods Mol Biol 1078:97-117
Dionne, Kalen R; Galvin, John M; Schittone, Stephanie A et al. (2011) Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection. J Neurovirol 17:314-26
Dionne, Kalen R; Leser, J Smith; Lorenzen, Kristi A et al. (2011) A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition. Exp Neurol 228:222-31
Berens, Heather M; Tyler, Kenneth L (2011) The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis. J Virol 85:3858-71
Beckham, J David; Tuttle, Kathryn D; Tyler, Kenneth L (2010) Caspase-3 activation is required for reovirus-induced encephalitis in vivo. J Neurovirol 16:306-17
Tyler, Kenneth L; Leser, J Smith; Phang, Tzu L et al. (2010) Gene expression in the brain during reovirus encephalitis. J Neurovirol 16:56-71
DeBiasi, Roberta L; Robinson, Bridget A; Leser, J Smith et al. (2010) Critical role for death-receptor mediated apoptotic signaling in viral myocarditis. J Card Fail 16:901-10
Levi, Marilyn E; Quan, Dianna; Ho, Joseph T et al. (2010) Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients. Clin Transplant 24:223-8
Tyler, Kenneth L (2009) Emerging viral infections of the central nervous system: part 2. Arch Neurol 66:1065-74
Beckham, J David; Tuttle, Kathryn; Tyler, Kenneth L (2009) Reovirus activates transforming growth factor beta and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection. J Virol 83:5035-45

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