Therapeutic potential of antiplatelet drugs to directly regulate human smooth muscle function
Heart attacks occur when a blockage called a thrombus develops in the blood vessels of the heart. Platelets are involved in thrombus development and can be switched on to become sticky by a wide variety of mediators including ADP which activates platelets through specific receptors, including the P2Y12 receptor (P2Y12R) expressed on the platelet surface. The P2Y12R is a key player in primary haemostasis and in arterial thrombosis, and consequently an established target of antithrombotic drugs1. Although the clinical benefits of P2Y12R antagonists are largely believed to be driven by their antiplatelet activity there is increasing evidence that the P2Y12R is also expressed on other vascular cell types2. Vascular smooth muscle cells (VSMCs) are important regulators of vessel tone and are involved in vascular inflammation, atherosclerosis, and restenosis following angioplasty. Studies have now demonstrated the presence of the P2Y12R in VSMCs with increased expression in coronary atherosclerotic plaques, which upon activation are implicated in human VSMC contraction and release of proinflammatory mediators3-5.
Little is known about the impact of P2Y12R antagonism upon VSMC behaviour or the molecular determinants regulating P2Y12R signalling and surface receptor expression in VSMCs. In this project you will characterize the molecular mechanisms regulating P2Y12R function, the consequences of changes in P2Y12R activity upon SMC behaviour and examine the ability of clinically used P2Y12R antagonists to modulate downstream receptor signalling in VSMCs. This study will significantly improve our understanding of why P2Y12R expression is enhanced in regions of vascular damage, with the potential for the development of new, more effective and safer drugs for the treatment and prevention of cardiac disease or make for a more informed use of pre-existing therapies
This project is for self-funding students only as there is no funding attached. Although it states 'Applications accepted all year round' we do encourage that the course commences either in January, April, July or September.
To apply you need to choose: Faculty of Biomedical Sciences under the ’Faculty’ section, School of Physiology and Pharmacolgy (PhD) under the ’programme choice’ section. Additionally under the ’Research Details’ section, please indicate that you are applying for a self funded project and give the project title and names of supervisors.
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Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal. 2012;8(3):609-619.
Wihlborg AK, Wang L, Braun OO, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol. 2004;24(10):1810-1815.
Rauch BH, Rosenkranz AC, Ermler S, et al. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol. 2010;30(12):2434-2442.
West LE, Steiner T, Judge HM, Francis SE, Storey RF. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res. 2014;102(3):429-35.