RhoA-ROCK-II and PKC signalling in CNS remyelination

Injury to oligodendrocytes is a common feature of a variety of neurological disorders, most notably the neuroinflammatory/degenerative disorder multiple sclerosis (MS). While most existing MS treatments target the generation of demyelinating lesions, there are none that currently address the repair of myelin sheaths. Animal and patients studies indicate that myelination contributes to long term axonal integrity. There is evidence that in a proportion of patients remyelination fails because of a failure of endogenous oligodendrocyte precursor cells (OPCs) to differentiate into remyelinating oligodendrocytes. Thus, the regulation of OPC differentiation in remyelination represents a critical question. Preliminary data included in the application suggests that myelin inhibitors of OPC differentiation regulate Rho-ROCK and PKC signalling and that both cascades can be beneficially modulated to induce OPC differentiation in the presence of myelin inhibitors in vitro by pharmacological inhibition. Consequently, I propose to test the hypothesis that inhibition of ROCK and PKC is able to promote remyelination in vivo.

Injury to oligodendrocytes is a common feature of a variety of neurological disorders, most notably the neuroinflammatory/degenerative disorder multiple sclerosis (MS). While most existing MS treatments target the generation of demyelinating lesions, there are none that currently address the repair of myelin sheaths. Animal and patients studies indicate that myelination contributes to long term axonal integrity. There is evidence that in a proportion of patients remyelination fails because of a failure of endogenous oligodendrocyte precursor cells (OPCs) to differentiate into remyelinating oligodendrocytes. Thus, the regulation of OPC differentiation in remyelination represents a critical question. Preliminary data included in the application suggests that myelin inhibitors of OPC differentiation regulate Rho-ROCK and PKC signalling and that both cascades can be beneficially modulated to induce OPC differentiation in the presence of myelin inhibitors in vitro by pharmacological inhibition. Consequently, I propose to test the hypothesis that inhibition of ROCK and PKC is able to promote remyelination in vivo.