Harnessing GPR17 Biology For Treating Demyelinating Disease

Abstract

Abstract : Multiple sclerosis (MS) is a devastating demyelinating disease in the CNS. We have recently identified a new G-protein coupled receptor 17 (GPR17), whose activation was shown to inhibit myelination. In this study, we hypothesize 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 MS models including cuprizone- and EAE- induced demyelination. During the funding period 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 preliminary study showed that GPR17 deletion may have a protective role during cuprizone-induced demyelination and enhances remyelination as well as in EAE model of MS. Moreover, we found that GPR17 agonists inhibit OPC differentiation while GPR17 antagonists enhance oligodendrocyte differentiation in culture. These preliminary studies provide us a strong basis to pursue drug-based treatment of the demyelinating diseases.