Project R-7266

Oncostatin M-induced astrocytic TIMP-1: the key to central nervous system lesion repair (Research)

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system, in which destruction of myelin sheaths leads to disturbed neuronal signaling. Available MS therapies modulate the immune response, but at best delay transition to the progressive phase. There is an urgent need for therapies that can reverse the permanent neurological damage. Oncostatin M (OSM), produced upon CNS injury, is a possible candidate to induce CNS repair. We already revealed that CNS-targeted OSM expression in mouse models of MS strongly suppresses autoimmune-mediated CNS damage and re-establishes remyelination. TIMP-1, produced by astrocytes, is strongly upregulated in these mouse models after OSM treatment and has already been linked to BBB and myelin pathology. Therefore, I hypothesize that OSM induced astrocytic TIMP-1 is a crucial regulator of repair in the damaged CNS by first line protection at the level of the BBB and by promoting remyelination. I investigate my hypothesis through the use of both in vitro cell culture systems and knockout mice. To provide translational relevance, a pathological study using port-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 effective new strategies in the treatment of progressive MS.

01 October 2016 - 30 September 2018