Molecular and structural characterisation of rare GPCR genetic variants in patients with impaired haemostasis

Blood clotting requires recruitment of platelets (specialised blood cells) to the site of injury to prevent bleeding. Platelet G-protein-coupled receptors (GPCRs) are critical regulators of platelet function where these receptors can be blocked for therapeutic intervention to treat and prevent blood clotting associated with atherosclerosis and stroke. A number of mutations in platelet GPCRs have been identified by sequencing in patients with abnormal bleeding and platelet dysfunction. To understand the molecular consequences of these mutations on G-protein-coupled receptor-mediated signalling in this cohort of patients, genetic, structural and pharmacological approaches will be applied which may allow tailoring of drug therapies in such patients. The student will combine molecular pharmacology, cell biology and advanced microscopy approaches to characterise the impact of mutations on biogenesis and signalling of the receptors involved in blood clotting, and evaluate a possibility of their pharmacological rescue. The advanced microscopy will be complimented with machine learning to improve sub-cellular localisation of GPCRs under investigation in high-throughput experiments.  

This is a cross-institutional and multi-disciplinary project between the Universities of Birmingham and Nottingham, and further enhances an existing collaboration as a result of the Centre of Membrane Proteins and Receptors (COMPARE), a unique collaboration between the Universities of Birmingham and Nottingham. This is an exciting collaboration between the Morgan and Veprintsev labs, including early career research Dr. Eline Koers, and includes machine learning experts Krull and Styles who would contribute their expertise in ML based image analysis. The student, while primary based in Birmingham, will be expected to spend 6 - 12 months at the UoN, combining both short- and long-term visits. This multidisciplinary project between the 5 investigators with complementary research areas of molecular genetics of bleeding disorders (Morgan) with structural and biophysical pharmacology of G protein-coupled receptors (GPCRs) (Veprintsev), GPCR biogenesis (Koers), and ML based methods for microscopy image analysis (Styles, Krull), as well as the industrial experience gained at Z7 Bio (Sykes). With the wide-ranging laboratory techniques employed the PhD student will have an excellent training during their studies and with the added experience of working in two very different research laboratories, and on the interface of the wet-lab and computational ML approaches.

Person Specification

Applicants should have a strong background in Biological Sciences, and ideally a background in genetics and molecular and cell biology. They should have a commitment to research in discovery and translational science and hold or expect to obtain at least 2:1 Degree in a relevant subject. 

How to apply

To apply, please download and complete all documentation available at https://more.bham.ac.uk/mrc-aim/phd-opportunities/ and send completed application to [Email Address Removed]

 Informal enquiries should be directed to Professor Neil Morgan ([Email Address Removed]) or Professor Dmitry Veprintsev ([Email Address Removed])

AIM DTP

The MRC Advanced Interdisciplinary Models (AIM) Doctoral Training Partnership (DTP) is a multi-institutional DTP between the Universities of Birmingham, Leicester and Nottingham. You will be based at the institution of the first supervisor. More information about the DTP is here