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Harnessing GPR17 Biology For Treating Demyelinating Disease
Revised annual rept. 8 Sep 2010-7 Sep 2011
TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER
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Multiple sclerosis MS is a devastating demyelinating disease in the CNS. We have recently discovered a new G-protein coupled receptor 17 GPR17, whose activation was shown to inhibit myelination. In this project, we hypothesize that that GPR17 signaling activation results in blockade of remyelination. The specific aims of this study are 1 to delineate the role of GPR17 in murine MS models of demyelinating diseases and 2 to test the therapeutic potential for GPR17 agonists and antagonists in two MS models. During the first year of this project, we used cuprizone-induced demyelinating animal model to analyze the GPR17 function in remyelination. We evaluated the dynamics of GPR17 expression, and examined control and GPR17 null mice over the course of demyelination and remyelination process. Our study showed that deletion of GPR17 has a protective role during cuprizone-induced demyelination and enhances remyelination. Moreover, we found that GPR17 agonists inhibit OPC differentiation while GPR17 antagonists enhance oligodendrocyte differentiation in culture. These studies provide us a strong basis to pursue drug-based treatment of the demyelinating animal model during the next year of the project as outlined in the original proposal.
APPROVED FOR PUBLIC RELEASE