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Serine Proteases and Pathophysiology of the neurovascular Unit (SP2U)” Since 2005, the INSERM group “tPA in the working brain” has been hosted at the GIP Cyceron «Centre for Brain Imaging and Research in Neurosciences» in association with the school of medicine and the University of Caen Basse-Normandie. Cyceron is a Cerebral Imaging Centre for Research in Neuroscience with two major axes of research, namely “the molecular and cellular bases of neuropathologies” and “the neural bases of cognition”. The current axis of research is targeted towards the understanding of the molecular and cellular mechanisms by which serine proteases (SP) may influence neuronal fate both in health and disease, with a particular emphasis on tissue-type plasminogen activator (tPA) and plasmin formation under pathological conditions (especially following cerebral ischaemia). Caen is a leader group in the field with several major findings these last few years: They have demonstrated, for the first time, that tPA is capable to potentiate NMDA signalling and should be considered as a new type of neuromodulator of the glutamatergic signalling; that both endogenous and exogenous tPA are neurotoxic following cerebral ischemia in animal models, that tPA crosses the intact blood-brain barrier both in vitro and in vivo and that it is possible to prevent this deleterious effect of tPA on neurotoxicity by immunotherapy.
Role in ProjectOur team will coordinate WP01 and take part in WP04, 07, 08 and 09. We will develop competitors of both tPA/LRP (LDL-related receptor protein) and tPA/NMDA receptors interaction, to prevent the ability of vascular tPA in reaching the brain parenchyma and of both vascular and endogenous parenchyma tPA to promote NMDA receptors-mediated neurotoxicity. We will also develop a method of immunotherapy that targets the neurotoxic effect of tPA in a mouse model of thromboembolic stroke with reperfusion in mice. Third, we will investigate whether release of circulating microparticles could be use as biomarkers.criteria to evaluate the risks of both hemorrhage and neurotoxicity in stroke patients. Finally, we will develop models of thromboembolic stroke containing a fibrin clot rich in plateletsand blood cells as an original model to test the efficacy of reperfusion. In addition of the tasks described above, we will evaluate a set of alternative or combined strategies for stroke both in vitro and in vivo.
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