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Project summary

The development of a blood clot in the cerebral circulation (ischaemic stroke) is the third most common cause of death and the most common cause of adult disability globally. Ischaemic injury occurs as a consequence of reductions in blood flow, with the longer the brain stays hypoperfused, the greater the damage inflicted. The central goal of stroke therapy is the prompt reperfusion of occluded blood vessels to minimise tissue death.

The delivery of fibrinolytic agents modelled on tissue-type plasminogen activator (t-PA) is the only clinically approved means available to stroke patients. Despite this, the use of t-PA is associated with significant side effects, limiting its widespread use. We are working on several novel approaches to improve upon existing stroke therapies, making them safer and more effective. Ongoing studies using a novel mouse model of thrombolysis (iCAT) developed in our lab will determine whether cerebral damage and cognitive impairment associated with stroke are reduced using these novel approaches.

While it is broadly accepted that restoration of blood flow to the brain will limit the progression of cell death and improve patient outcome after stroke, there is evolving evidence that reopening the blocked artery (recanalisation) does not always lead to reperfusion of the small vessels of the brain. Failure of cerebral reperfusion correlates with worse prognosis for stroke patients, however the underlying mechanisms leading to continued hypoperfusion despite recanalisation of larger blood vessels is poorly understood. We are investigating the causes of cerebral hypoperfusion, in an attempt to identify additional targets for potential new stroke therapies.

Papers

1. Jackson SP and Schoenwaelder SM. Nat Rev Drug Discov, October, 2(10): 775-789, 2003.

2. Jackson SP, et al, Nat Med, 11(5):507-514, 2005.

3. Schoenwaelder SM, et al, J Biol Chem, 282(39):28648-58, 2007.

4. Simone M Schoenwaelder, et al, J Biol Chem, 285(4):2886-2896, 2010.

5. Andre L. Samson, et al, Sci Rep. 2015 Nov 4; 5:16171. doi: 10.1038/srep16171.

6. Andre L Samson, et al; Blood 2017, Dec 7;130(23):2453-2462. doi: 10.1182/blood-2017-06-789032. Epub 2017 Oct 26. Selected as a Plenary Paper

​7. Shaun P. Jackson and Simone M. Schoenwaelder, J Thromb Haemost, 10(10): 2123-2126, 2012.