The overall goal of the research is to define the role of the cellular stress response in the modulation of viral infection of the central nervous system (CNS) using canine distemper virus (CDV) encephalitis as a model. Objective 1 will define the basis for stress response-induced alterations in CDV RNA metabolism and confirm the broader applicability of these phenomenon using measles virus (MV). The role of 72kDa heat shock protein (72k HSP) as a transcriptional cofactor for CDV will be established, the effect of cellular stress on CDV mRNA half life determined, and the relevance of cellular stress to MV mRNA metabolism documented. Objective 2 will establish the in situ role of HSP7O proteins in stress-mediated alterations of virus infection phenotype using translational inhibition of 72k and 73k HSP. Objective 3 will determine the effect of stress-induced alterations in CDV RNA metabolism on viral phenotype in canine cerebellar explant cultures, a cell system which is physiologically more relevant to CNS infection. Hyperthermic and cytokine induction of the stress response will be used to dissect the paradoxical relationship between the cytoprotective effects of 72k HSP and the promoting effects on virus infection. The specific role of 72k HSP in mediating these stress response-mediated events will be determined by antisense inhibition of 72k HSP expression. Future in vivo studies can determine how immune clearance mechanisms modulate the outcome of virus- stress response interaction. Establishing a protective or detrimental role of the CNS stress response in viral encephalitis will provide a basis for therapeutic intervention based upon HSP modulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS001798-03
Application #
2379489
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1995-05-01
Project End
2000-02-29
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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