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  Modulating platelet reactivity to reduce the risks of heart attacks in acute coronary syndrome patients

   School of Physiology, Pharmacology & Neuroscience

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  Prof Stuart Mundell  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Heart disease is the leading cause of death worldwide accounting for one-third of deaths. Platelets play a central role in acute coronary syndromes (ACS) through the development of arterial thrombosis. Although pharmacological blockade of the platelet P2Y12 receptor (P2Y12R) forms a powerful therapeutic tool in reducing the risk of heart attacks in ACS therapeutic benefits are compromised by variable levels of receptor inhibition. Weak P2Y12R inhibition is associated with increased risk of heart attack whilst conversely strong inhibition is associated with patient bleeding. Fine tuning the level of platelet inhibition in these two extremes has obvious therapeutic potential to improve patient survival with a marked inter-individual variability in the degree of platelet inhibition seen in the clinic. A significant proportion of patients demonstrate either high or low platelet reactivity with an associated risk of thrombotic or bleeding events, respectively. Potentially patients at high risk of bleeding may be better managed through a switch to less aggressive antiplatelet therapy to reduce this risk

Studies from our laboratory have established that one drug previously labelled as an antagonist ticagrelor is actually an inverse agonist at the P2Y12R (Aungraheeta et al., 2016).  Ticagrelor is able to reduce agonist-independent signalling which may in part explain the therapeutic efficacy of ticagrelor but also its increased tendency to promote patient bleeding. The main aim of this project is to fully understand how ticagrelor and other inverse agonists bind to the P2Y12R to modulate receptor activity. In order to address this you will use a combination of computational modelling, in cell signalling approaches and immunofluorescent confocal microscopy to define how these drugs affect changes in receptor activity and expression.

These studies will help us understand how these antiplatelet drugs modulate receptor activity and expression improving our understanding of their therapeutic usefulness in patients suffering from arterial thrombosis.

Medicine (26)

Funding Notes

This project is available to international students who wish to self-fund their PhD or who have access to their own funding. Please contact Dr Mundell directly for information about the project and how to apply ([Email Address Removed]).

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