Projects per year
G protein-coupled receptor function and signalling in atherothrombosis
G protein-coupled receptors (GPCRs), one of the largest protein families in the human genome, are the most tractable set of therapeutic targets for novel drug design. These cell surface expressed proteins translate extracellular cues which bombard the cell surface into signals which determine cellular function. GPCRs are regulated in a dynamic and complex manner, and are not static entities inserted into the plasma membrane of cells. My research examines the cell specific signals produced by individual GPCRs and the complex regulatory mechanisms controlling GPCR signalling, surface expression and intracellular sorting. Further my research assesses the impact of such mechanisms on signalling pathways that initiate important physiological responses. In order to examine these questions we use both biochemical and imaging techniques to study receptor movement and function.
At present our research is concentrated on GPCR function in a number of cells which maintain the integrity of the cardiovascular system including platelets and smooth muscle cells. Platelets are an essential element in the pathophysiology of heart disease with platelet expressed GPCRs clinically useful pharmacological targets for antithrombotic drugs. Our research in platelets has three major strands.
Characterization of the molecular mechanisms that regulate the function of GPCR signalling in platelets.
Alterations in the responsiveness of platelet GPCRs have important consequences on platelet function with mechanisms, including desensitization, internalization and subsequent endocytic sorting regulating their function (Hardy et al., 2005; Mundell et al., 2008; Nisar et al., 2011, 2012, Cunningham et al., 2013). Our studies continue to examine the molecular mechanisms underlying the control and traffic of platelet GPCR whilst determining the consequences of such mechanisms on receptor function. A number of different techniques are employed to answer these questions ranging from measurement of cellular signalling pathways through to immunofluorescent imaging of single cells.
Genotyping and phenotyping platelet receptor function
This research seeks to identify the faulty genes that underlie bleeding in families with abnormal blood platelet function. The study of patients with bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets. Ultimately, this work is anticipated to identify novel platelet proteins that are targets for development of anti-thrombotics and to facilitate the wider use of antiplatelet agents in the fight against heart disease by exclusion of patients with platelet defects. This research has already identified mutations in a number of platelet GPCRs including the P2Y12 (Daly et al., 2009 and Nisar et al., 2011) and TxA2 receptor (Mumford et al., 2010 and Gaussem et al., 2013) that change receptor function and contribute to the bleeding tendency in specific individuals. Ongoing studies continue to identify mutations in other platelet expressed GPCRs and in the proteins that regulate receptor function.
Characterize the molecular mechanisms of currently used antithrombotics in the patient population
In collaboration with clinical colleagues in the Bristol Heart Institute and industrial collaborators we examine the interaction between and molecular mechanisms of therapies in the treatment of thrombosis, concentrating on those which inhibit platelet reactivity. The goal of this research is to help refine the clinical use of these therapeutics by fully defining their mode of action both on their target receptor and then on their ability to impact the signalling of other platelet expressed GPCRs.
In summary this body of work aims to provide fundamental new insights into the molecular mechanisms regulating platelet receptor function leading to the development of new, more effective and safer drugs for the treatment and prevention of cardiac disease or making for a more informed use of pre-existing therapies.
- G protein-coupled receptor
- Molecular modelling
- Cell Signalling
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1/09/16 → 31/08/18
Tetherin/BST2, a physiologically and therapeutically relevant regulator of platelet receptor signallingZhao, X., Alibhai, D. R., Khalil, J. S., Williams, C. M., Li, Y., Sessions, R. B., Cross, S., Seager, R. A., Aungraheeta, M. S. R. H., Leard, A. D., McKinnon, C. M., Phillips, D. J., Poole, A. W., Banting, G. S. & Mundell, S. J., 13 Apr 2021, In: Blood Advances. 5, 7, p. 1884–1898 15 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile42 Downloads (Pure)
Pharmacodynamic Comparison of Ticagrelor Monotherapy Versus Ticagrelor and Aspirin in Patients After Percutaneous Coronary Intervention: The TEMPLATE (Ticagrelor Monotherapy and Platelet Reactivity) Randomized Controlled TrialJohnson, T. W., Baos, S., Collett, L., Hutchinson, J. L., Nkau, M., Molina, M., Aungraheeta, R., Reilly-Stitt, C., Bowles, R., Reeves, B. C., Rogers, C. A., Mundell, S. J., Baumbach, A. & Mumford, A. D., 15 Dec 2020, In: Journal of the American Heart Association. 9, 24, p. e016495
Research output: Contribution to journal › Article (Academic Journal) › peer-review
Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleedingMundell, S. J., Rabbolini, D., Gabrielli, S., Cheng, Q., Aungraheeta, R., Hutchinson, J. L., Kilo, T., Mackay, J., Ward, C. M., Stevenson, W. & Morel-Kopp, M-C., 1 Jan 2018, In: Journal of Thrombosis and Haemostasis. 16, 1, p. 44-53 10 p.
Research output: Contribution to journal › Article (Academic Journal) › peer-reviewOpen AccessFile18 Citations (Scopus)215 Downloads (Pure)
- 1 Fellowship awarded competitively
Senior Basic Science Research Fellowships - Role of G protein-coupled receptor sorting in platelet function.
Stuart J Mundell (Recipient)1 Aug 2011 → 1 Aug 2016
Activity: Other activity types › Fellowship awarded competitively