Project R-6303

Oncostatin M as a master regulator of central nervous system lesion repair (Research)

Multiple sclerosis is a chronic disabling disease of the central nervous system, in which destruction of myelin sheaths leads to disturbed neuronal conduction. Available MS therapies modulate the immune response, but at best delay transition to the progressive phase. There is an urgent need for therapies that in addition promote CNS repair. Oncostatin M (OSM), a neuropoietic cytokine, is produced upon CNS injury. OSM signals through the LIF receptor (LIFR), thereby promoting survival of specialized brain cells, and by reducing myelin breakdown. In addition, OSM signals through its specific receptor, OSMR. Our data show that CNS-targeted OSM expression in a mouse model of MS strongly suppresses autoimmune-mediated CNS damage, much more potent than LIF. By signalling through both the LIFR and OSMR, OSM is expected to have a superior therapeutic potential as LIF. I hypothesize that - upon CNS damage - OSM is a crucial regulator of de- and remyelination by inducing a beneficial astroglial and innate immune response. To investigate this hypothesis, I make use of a unique combination of in vitro cell culture systems and cell specific knockout mice. To provide translational relevance, a pathological study using post-mortem MS brain material is performed. The results of this project provide increased insights into the complex processes of CNS lesion development and repair, and aid in the quest for promising new strategies in the treatment of progressive MS.

01 October 2015 - 30 September 2016