In prior studies funded by this grant, we established that the oligodendroglial lineage is vulnerable to non-N-methyl-D-aspartate glutamate receptor (non-NMDA-GluR)-mediated excitotoxic necrosis. Meanwhile, others reported that inhibitors of ionotropic GluR diminish severity of experimental autoimmune encephalomyelitis (EAE). During the new granting period, we will determine the properties and composition of the ionotropic GluR that mediate oligodendroglial excitotoxicity, and the role of excitotoxicity in killing oligodendroglia and neurons in mice with EAE elicited by immunization with myelin oligodendrocyte glycoprotein (MOG). A novel and powerful aspect of our studies is the use of mouse strains in which oligodendroglia and neurons have been genetically modified to enhance their in situ visibility, or to alter the permeability properties of their non-NMDA-GluR. These include transgenic mice that express enhanced green fluorescence protein (EGFP) in the oligodendroglial lineage, driven by 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase) promoters; transgenic mice that express yellow fluorescence protein (YFP) in motor neurons, driven by the thy1 promoter; and mice lacking functional copies of the gene encoding non-NMDA-GluR GluR2 subunits. Our results will illuminate mechanisms of injury to target oligodendroglia and neurons in EAE, and should prove helpful in determining whether ionotropic GluR inhibitor treatment trials are justified in patients with multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025044-22
Application #
7260364
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Utz, Ursula
Project Start
1987-09-01
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
22
Fiscal Year
2007
Total Cost
$298,970
Indirect Cost
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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