ESR 1: Regulation of GPVI clustering: role of the cytoskeleton

Host: University of Birmingham, UK

Supervisory team: Natalie Poulter and Steve Watson (University of Birmingham); Bernhard Nieswandt (University of Würzburg)

Project locations: University of Birmingham, UK (Year 1 & 3), University of Würzburg, Germany (Year 2), University of Rijeka, Croatia (2 months in Year 1)

Joint PhD Degree: University of Birmingham and University of Würzburg

Project details: The platelet receptor GPVI has been identified as a promising anti-thrombotic target so it is important to understand how GPVI signalling is regulated. Interaction with its ligands causes GPVI to cluster and this can be visualised with advanced microscopy techniques1. The actin cytoskeleton is known to play a role in receptor clustering in many cell types but its role in GPVI clustering has not been studied. Work using knock mouse models of a small GTPase Rac1, which is involved in regulating actin, has shown that Rac1 is required for proper GPVI signalling and thrombus formation2. We hypothesise that this is through regulation of GPVI clustering. In this project we will investigate the role Rac plays in GPVI clustering in human platelets using Rac inhibitors and single molecule microscopy techniques (Birmingham). Studies will be extended into mouse platelets using knock out mouse models of Rac1 and other cytoskeleton proteins (Würzburg). Biochemical techniques will be used to investigate how this influences downstream signalling events. The effect on clustering of novel biologics or small molecule inhibitors generated by other ESRs in TAPAS will be tested. Training in alternative methods for studying receptor-cytoskeleton interactions will be received through a secondment to University of Rijeka, Croatia.

References: Poulter et al (2017). Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets J Thromb Haemost. 15(3):549-564

Pleines et al. (2009). Rac1 is essential for phospholipase C-γ2 activation in platelets Pflugers Arch – Eur J Physiol, 457: 1173

 Desirable student skills: Biophysics, Cell biology, Biochemistry, an interest in microscopy, an aptitude for maths/coding/computer science, willingness to work with animal models.

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