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A new role for the Gelsolin family in the regulation of G protein-coupled receptors (GPCR) activity

The aim of the project is to explore the role of the Gelsolin family across different GPCR pathways to identify if interaction is unique to PAR4 or a universal regulator of GPCRs.

Number of places

1

Opens

1 June 2017

Eligibility

2:1 UK Honours degree or overseas equivalent.

Project Details

Key words: G protein-coupled receptors, proteinase activated receptors, pharmacology, cell biology Research Group: New Medicines Fundamentals, New Medicines Target Validation

 

Thrombin regulates haemostasis and pathophysiological coagulation in response to vascular injury. In response to vessel damage, release of thrombin into the circulation irreversibly activates a family of G-protein-coupled receptors (GPCRs) called proteinase-activated receptors (PARs). Activation of PAR1 and PAR4 by thrombin is responsible for platelet activation and vascular inflammation, which makes them attractive therapeutic targets. 


Rare genetic variants in PAR4 have been identified in patients with loss of platelet function. Our studies have revealed interesting structure-function relationships of genetic variants in regulation of PAR4 activity [1]. Pilot proteomic analysis of human PAR4 versus PAR4 variant expression has revealed a new paradigm for GPCR regulation (unpublished). PAR4 association with key Gelsolin family members [2] increased more than three-fold when variant PAR4 was expressed. This is the first time GPCR interactions with Gelsolin proteins have been reported. 

Here we propose to study the role of the Gelsolin family in regulating the activity of various GPCRs including β2-adrenergic receptor, purinergic receptors (P2Y1 and P2Y12) and PARs (PAR1, PAR2 and PAR4). Receptor pharmacology and endosomal trafficking will be assessed in mammalian cell lines with key Gelsolin members overexpressed or depleted

Supervisor

Dr Margaret Cunningham

Contact us

How to apply

Applicant can apply by completing the online application form https://ben.mis.strath.ac.uk/pguserprofile/control/enterDetailsPage