SP18 Cobl and stroke

SP18 The actin nucleator Cobl as target in excitotoxicity induced by ischemic stroke

Project leaders: Christiane Frahm, Britta Qualmann

Background and previous work
Ischemic stroke is a consequence of impaired cerebral blood supply, leading to a depletion of oxygen and energy, a strong release of the excitatory neurotransmitter glutamate and a massive calcium influx. Strikingly, our preliminary collaborative analyses experiments suggest the actin nucleator Cobl as target in excitotoxicity induced by ischemic stroke: At neurotoxic glutamate levels, the resulting high Ca2+ concentrations affected Cobl protein levels. Thus, modulation of Cobl levels may be an adaptive reaction to the neurotoxic stress caused by stroke.

Specific aims and working programme
Based on our preliminary data revealing stroke-mediated changes in Cobl levels we propose to apply the MCAO stroke model (occlusion of the middle cerebral artery) to address the time course of post-ischemic reduction of Cobl protein and mRNA levels. Inducing excitotoxicity in neuronal cell cultures, we will study the concentration- and time-dependence of Cobl regulation and aim at identifying the underlying signalling pathways. Finally, we will determine effects of Cobl knock-out on the severity of pathophysiological effects associated with ischemic stroke and address whether increasing Cobl levels is able to counteract excitotoxic effects on structural disintegration of neurons.
Our studies will provide insights into how neurons respond to ischemia, aim at establishing the actin nucleator Cobl as a critical component onto which excitotoxicity-dependent signals converge. This Cobl-mediated adaptive stress reaction might be involved in post-stroke plasticity by a structural and functional reorganisation of the brain.