ESR 4: Role of (patho)physiological flow on receptor clustering and signalling

Host: Universiteit Maastricht, The Netherlands

Supervisory team: Johan Heemskerk and Yvonne Henskens (Maastricht University), Steve Watson and Natalie Poulter (University of Birmingham), Dmitry Kashanin (Cellix)

Project locations: Maastricht University NL (Year 1 and 3); University of Birmingham UK (Year 2); Cellix Ltd. Dublin IRE (6 months in Year 3)

Joint PhD Degree: Maastricht University and University of Birmingham

Project details: In this project, we will establish how the clustering and signalling of GPVI and CLEC-2 determine platelet-platelet interactions in thrombus formation and structure under (pathological) flow conditions using microfluidics. Starting from an established multiparameter method of whole-blood thrombus formation, conditions will be established of high/low GPVI or CLEC-2 signalling, and these will be related to thrombus buildup and dynamics. The concept herein is that of a ‘multilayered thrombus tissue’, as opposite to that of a ‘monolayered platelet tissue’, as required for the role of platelets in vascular integrity (Maastricht NL). Super-resolution microscopy will then be used to quantify the extent of GPVI and CLEC-2 clustering and signalling at the established flow conditions, and compared to clustering under static conditions (Birmingham, UK). The high-end resolution microscopy will furthermore provide more detailed insight into the heterogeneous buildup of the ‘thrombus tissue’. Subsequently at Cellix (Dublin IRE), and later in Maastricht, the gained expertise will be used for development of commercial microfluidic flow chambers for drug testing. Here, the receptor roles in thrombus formation will be assessed by using: (i) established antithrombotic drugs, and (ii) the biologics and small molecules developed in TAPAS.

Desirable student skills: Biomedicine, Medical Biology, knowledge of/interest in microfluidics technology

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