autophagySTROKE

autophagySTROKE, ANR 2023.
Project coordinator:
Dr Benoit Roussel, INSERM U1237, Blood and Brain Caen Normandie Institute, Caen, France.
Project Partner :
Dr Jerome Parcq, Op2Lysis, centre Cyceron, Caen, France.

Stroke is caused by a sudden decrease of cerebral blood flow following the blockage of a brain artery. Today, the aim of the medical management is to limit brain damages by inducing the recanalization of the occluded artery. To date, thrombolysis by tissue type plasminogen activator (tPA) is the only pharmacological treatment available for the acute phase of ischemic stroke. However, this treatment presents some side effects including a risk of haemorrhagic transformation. In the brain, tPA is involved in various pathophysiological functions. We have several evidences showing that tPA is involved on inflammatory process in the brain after stroke and also can modulate a cellular mechanism called autophagy, which is responsible of protein degradation. We hypothesise that a part of the deleterious effect of tPA administration is due to its effect on the inflammatory responses, especially on the mechanisms of immune cells infiltration into the brain and that it is due to its ability to modulate autophagy in endothelial cells. We also aim to understand if the modulation of immune cell infiltration by tPA worsens the risk of haemorrhagic transformation. The aim of our project is to understand how tPA exert its deleterious inflammatory effects to propose new therapeutic strategy, OptPA, to improve stroke treatment. The objectives of our project are (1) to elucidate the mechanism(s) and consequences of tPA action on endothelial cells during inflammation associated to ischemic stroke (2) to investigate the effect of OptPA to alleviate deleterious effect of tPA on inflammatory response and haemorrhagic transformation. The overall aim of this project is to provide an extensive insight into the physiopathology of ischemic stroke and propose a strategy that improves thrombolysis outcome as a basis for clinical investigations by using a range of complementary techniques such as relevant in vitro and in vivo models combined to cutting edge imaging techniques.