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. 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 regulatory mechanisms controlling GPCR traffic whilst assessing 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.

Presently we are examining the regulation of P2Y1 and P2Y12 purinergic receptors in human platelets. Platelets are an essential element in the pathophysiology of heart disease. Adenosine diphosphate (ADP), which influences platelet adhesiveness and induces platelet aggregation, is recognised as one of the most important mediators of haemostasis and thrombosis. ADP activates two G protein-coupled ADP receptors, P2Y1 and P2Y12, to promote platelet aggregation. Indeed these receptors are pharmacological targets for antithrombotic drugs. Alterations in the responsiveness of ADP receptors are likely to have important consequences on platelet function and indeed evidence suggests that such mechanisms, including desensitization, internalization and subsequent endocytic sorting regulate their function. However little work has been performed to determine the underlying details of these mechanisms. Studies examining the molecular mechanisms underlying the control and traffic of these receptors whilst determining the consequences of such mechanisms on receptor function are ongoing. 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.


Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor.

Aungraheeta R, Conibear A, Butler M, Kelly E, Nylander S, Mumford A, Mundell SJ.

Blood. 2016 Dec 8;128(23):2717-2728. 


Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking.

Norman JE, Cunningham MR, Jones ML, Walker ME, Westbury SK, Sessions RB, Mundell SJ, Mumford AD.

Arterioscler Thromb Vasc Biol. 2016 May;36(5):952-60. 


Jones ML, Norman JE, Morgan NV, Mundell SJ, Lordkipanidzé M, Lowe GC, Daly ME, Simpson MA, Drake S, Watson SP, Mumford AD; UK GAPP study group.
Thromb Haemost. 2015 Mar 30;113(4):826-37.

Nisar SP, Jones ML, Cunningham MR, Mumford AD, Mundell SJ; UK GAPP Study Group.
Br J Pharmacol. 2014 Sep 18.

Kelly E, Mundell SJ, Sava A, Roth AL, Felici A, Maltby K, Nathan PJ, Bullmore ET, Henderson G.
Psychopharmacology (Berl). 2015 Jan;232(1):305-14. 

Patel YM, Lordkipanidzé M, Lowe GC, Nisar SP, Garner K, Stockley J, Daly ME, Mitchell M, Watson SP, Austin SK, Mundell SJ. 
J Thromb Haemost (published online)

Morphine-induced internalization of the L83I mutant of the rat μ-opioid receptor.

Cooke AE, Oldfield S, Krasel C, Mundell SJ, Henderson G, Kelly E.

Br J Pharmacol 2014  [Epub ahead of print]


A novel thromboxane A2 receptor N42S variant results in reduced surface expression and platelet dysfunction.

Nisar SP, Lordkipanidzé M, Jones ML, Dawood B, Murden S, Cunningham MR, Mumford AD, Wilde JT, Watson SP, Mundell SJ, Lowe GC; on behalf of the UK GAPP study group.

Thromb Haemost 2014


Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay.

Lordkipanidzé M, Lowe GC, Kirkby NS, Chan MV, Lundberg MH, Morgan NV, Bem D, Nisar SP, Leo VC, Jones ML, Mundell SJ, Daly ME, Mumford AD, Warner TD, Watson SP.

Blood 2014


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LAB MEMBERS
STUART MUNDELL

Principal Investigator

Professor

s.j.mundell@bristol.ac.uk


Publications

Stuart graduated from the University of Glasgow with a degree in Pharmacology in 1994. He then obtained his PhD from Bristol in 1998 with a thesis investigating G protein-coupled receptor regulation. After his PhD Stuart undertook post-doctoral positions in the laboratories of Professor Jeffrey Benovic in Philadelphia and Dr Eamonn Kelly in Bristol.  In 2003 Stuart was awarded a British Heart Foundation Intermediate Fellowship to investigate the molecular mechanisms regulating purinoceptor function in human platelets. In 2006 he was awarded a Basic Science Lectureship (2006-2011) from the British Heart Foundation to continue his research and allow him to establish his own laboratory.  Stuart was the recipient of the British Pharmacological Societies Bill Bowman lectureship in 2006 and Novartis Prize in 2010. He was promoted to Professor in August 2017.







PRESENT LAB MEMBERS



 

Lawrence Hutchinson


Post-doctoral researcher

jh13864@bristol.ac.uk







Lawrence completed a PhD in immunology at Cambridge that focused on bacterial interference with host cell trafficking. He then undertook post-doc work at the MRC's Centre for Reproductive Health, looking at inflammation resolution and potential roles for pathogen-induced myometrial inflammation in the initiation of pre-term labour. His platelet career began under the tutelage of Ingeborg Hers in Bristol, investigating PI3K effector function in human and mouse platelets. His current BHF-funded work for Stuart Mundell explores the role of purinergic receptors in the cardiovascular system.



PREVIOUS LAB MEMBERS




































 

XIAOJUAN (JENNA) ZHAO


Post-doctoral researcher

jenna.zhao@bristol.ac.uk

Publications




CARMEN COXON
 


Post-doctoral researcher



carmen.coxon@bristol.ac.uk

Publications

 

















































Carmen completed a biochemistry degree at the University of Bath in 2001. She obtained her PhD at the University of Reading where she worked on cardiac hypertrophy and regeneration. Carmen then moved to the University of Oxford to work with Dr Duncan Campbell from 2007 to 2012, investigating the ITIM receptor G6B and its role in platelet function. During this time, Carmen ran projects with collaborators across the university pertaining to drug discovery, drug repurposing, and reduction/oxidation biochemistry. Carmen then spent one year working in the laboratory of Professor Terence Rabbitts (FRS) at the Weatherall Institute of Molecular Medicine (Oxford) on a drug discovery project, before moving to Bristol in 2014 to work with Dr Stuart Mundell on novel regulators of purinergic receptor trafficking and regulation.  Carmen is now based at the Structural Genomics Consortium in Oxford.
 

 

RIYAAD AUNGRAHEETA

PhD student


riyaad.a.2012@bristol.ac.uk



Riyaad joined the lab as a PhD student in 2013 after obtaining a BSc in Biomedical Sciences from UWE and an MSc in the same field from the University of Bristol. His project focussed on the investigation of the molecular mechanisms of action antiplatelet drugs known as P2Y12 antagonists, in particular ticagrelor. He had his viva in December 2017 and is presently working for Professor Andrew Mumford.


Co-supervised group members: Jane Norman (Andrew Mumford's Group
jane.norman@bristol.ac.uk)Alex Cooke (Graeme Henderson's GroupAlex.Cooke@bristol.ac.uk)
Previous group members:  Shaista Nisar (Post-doctoral researcher, 2010-2015), Margaret Cunningham (Post-doctoral researcher, 2010-2014), Rob Pope (Post-doctoral researcher, 2010-2014, co-supervised by Alastair Poole), Mark Butler (PhD student, 2009-2013), Ian Stanton (PhD student, 2008-2012, co-supervised by Alastair Poole), Liz Emery (Wellcome Trust "Dynamic Cell Biology" PhD Student, 3 month Placement, Oct '10 - Jan '11)Amy Saber (MSc Biomedical Sciences Research Student 2009/10), Johanna Barton (PhD student co-supervised by Alastair Poole)