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Dr Margaret Rose Cunningham

Strathclyde Chancellor'S Fellow

Strathclyde Institute of Pharmacy and Biomedical Sciences

Personal statement

I am a Chancellor’s Research Fellow and Lecturer in New Medicines.  

I graduated with a First Class BSc (Hons) in Biochemistry and Pharmacology in 2006 from the University of Strathclyde.  In 2010 I then completed an AJ Clark British Pharmacological Society (BPS)-funded PhD studentship in pharmacology and cell biology at Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS).  After a four year postdoctoral research position in the Bristol Platelet Group (University of Bristol), I returned to SIPBS in 2014 as an independent Strathclyde Chancellor’s Research Fellow to establish my own laboratory. 

My field of expertise is G protein-coupled receptor (GPCR) regulation and function.  GPCRs are membrane proteins that are involved in a variety of physiological processes ranging from roles in the regulation of mood, blood clotting, obesity, cancer, inflammation and pain.  

The focus of my research is identifying targets for the development new or improved anti-platelet therapies. One target of interest is the GPCR family called proteinase-activated receptors (PARs), which are known to regulate thrombin activity in hemostasis and thrombosis. 

Two areas we are currently focusing on are:

  • Deciphering the protein interacting pathways that regulate PAR pharmacology to identify novel ways to regulate receptor activity for the development of new drugs.  
  • Screening novel synthetic PAR modulators to assess their pharmacology and determine their use as inhibitors of platelet function.

I am the Editor-in-Chief for Pharmacology Matters and a member of the British Pharmacological Society, the Biochemical Society and the British Society for Cardiovascular Research. I sit on the editorial board for Pharmacology Research & Perspectives.  I am part of the SIPBS Athena SWAN Self Assessment Committee and was involved in the renewal of the Athena SWAN Bronze Award. 

I am a Fellow of the Higher Education Academy (HEA) and a keen advocate of enhancing STEM education in primary schools.  I am a mentor for the Social Mobility Foundation and Widening Access at University of Strathclyde.  

Publications

Editorial for Pharmacology Matters
Cunningham Margaret
Pharmacology Matters Vol 10, (2017)
Protease-activated receptor 4 variant p.Tyr157Cys reduces platelet functional responses and alters receptor trafficking
Norman Jane E., Cunningham Margaret R., Jones Matthew L., Walker Mary E., Westbury Sarah K., Sessions Richard B., Mundell Stuart J., Mumford Andrew D.
Arteriosclerosis, Thrombosis, and Vascular Biology Vol 36, pp. 952-960, (2016)
http://dx.doi.org/10.1161/ATVBAHA.115.307102
Proteinase-activated receptors (PARs) as targets for antiplatelet therapy
Cunningham Margaret, McIntosh Kathryn, Bushell Trevor, Sloan Graeme, Plevin Robin
Biochemical Society Transactions Vol 44, pp. 606-612, (2016)
http://dx.doi.org/10.1042/BST20150282
Protease-activated receptor 2 : are common functions in glial and immune cells linked to inflammation-related CNS disorders?
Bushell Trevor J., Cunningham Margaret R., McIntosh Kathryn A., Moudio Serge, Plevin Robin
Current Drug Targets Vol 17, pp. 1861-1870, (2016)
http://dx.doi.org/10.2174/1389450117666151209115232
Identification and characterization of novel variations in platelet G-protein coupled receptor (GPCR) genes in patients historically diagnosed with type 1 von Willebrand disease : GPCR variations in type 1 von Willebrand disease
Stockley Jacqueline , Nisar Shaista P., Leo Vincenzo C., Sabi Essa , Cunningham Margaret R., Eikenboom Jeroen C., Lethagen Stefan, Schneppenheim Reinhard , Goodeve Anne C., Watson Steve P., Mundell Stuart J., Daly Martina E., null null
PLoS One Vol 10, (2015)
http://dx.doi.org/10.1371/journal.pone.0143913
Rare platelet G protein-coupled receptor variants : what can we learn?
Nisar S P, Jones M L, Cunningham M R, Mumford A D, Mundell S J, null null
British Journal of Pharmacology, (2015)
http://dx.doi.org/10.1111/bph.12941

more publications

Teaching

I am a lecturer for the Undergraduate Year 3 BM324 and BM327 Fundamentals of Pharmacology classes.  I also lecture on the BM933 Postgraduate Studies in Haematology and BM937 Postgraduate Studies in Drug Discovery programmes.

I have previously provided laboratory placements as part of the Erasmus programme and host final year BMS, MSc and MRes project students in SIPBS.

I actively engage with primary schools (P1-P7) to deliver STEM outreach and currently have a Biochemical Society outreach award to support a 'Pond Life' project with Lennox Primary in West Dunbartonshire. 

Research interests

I have a long-standing interest in the molecular mechanisms that control the behavior of G-protein coupled receptors (GPCRs).  GPCRs play an important role in clinical medicine due to their widespread distribution and the roles they play in pathophysiological processes. Human genome studies have identified a substantial number of genetic variants in GPCR families which result in dysregulation of normal receptor function (i.e. altered receptor expression, traffic and signal transduction).  The identification of particular polymorphisms cannot be credited as the sole contributing factor to any given disease.  However, phenotypic screening of patients harboring novel variants can provide mechanistic insight into the extent of endogenous receptor dysfunction in clinically relevant settings.  Knowledge of novel sites that alter receptor activity could be exploited for therapeutic advantage.  Targeting sites that offer a way to fine-tune receptor signaling pathways may improve pharmacological selectivity in the advancement of next generation GPCR drug development.   

     

 Overview

 

I am particularly interested in a family of GPCRs called Proteinase-Activated Receptors (PARs) which has four family members (PAR1-4).  In the cardiovascular system, these receptors are expressed at the surface of circulating cells (platelets, leukocytes) and smooth muscle cells (SMCs) and endothelial cells that comprise the vessel wall.  In response to vessel damage, release of thrombin into the circulation irreversibly cleaves PAR1, PAR3 and PAR4 expressed on these cells, resulting in receptor activation.  The actions of thrombin via these receptors promote platelet aggregation, endothelial angiogenesis, leukocyte infiltration, SMC migration and proliferation.  The roles of PARs, namely PAR1 and PAR4, in platelet activation and vascular inflammation have been well documented. 

 

 PAR activation

 

The crystal structure of PAR1 resolved in a complex with the PAR-1 selective antagonist Vorapaxar has recently reveal interesting structural features of the PAR family that are distinct from other GPCR structures.  The clinical use of this antagonist has recently been FDA approved in the treatment of a limited cohort of patients suffering recurrent acute coronary syndromes.  However the wider therapeutic promise of this drug has fallen short of desirable due to the severity of the associated bleeding and increased risk in cerebral haemorrhage. As yet, the development of selective antagonists which target the second thrombin receptor, PAR4, is less advanced. 

 

I am interested in identifying potentially targetable sites within PAR4 with the aim to understand the functional consequence of protein-protein interaction at these sites. Through the characterisation of discrete motifs that regulate PAR4 activity, the hope to delineate the pathways that bias receptor function towards a protective role in thrombin-mediated signal transduction.  Through successful collaboration I have been able to employ cutting edge techniques including proteomics and fluorescent imaging techniques, such as FRET, to detect and quantify protein-protein interaction.  In addition to a range of biochemical approaches, my laboratory also uses multi-mode plate-reading technology (BMG Labtech POLARstar Omega, and Molecular Devices Flexstation III) for performing fast kinetic and end point cell based assays to measure receptor activity.   

Professional activities

Pharmacology Matters (Journal)
Editor
1/7/2017
The Academy of Medical Sciences (AMS) - Shaping your career in research
Invited speaker
6/6/2017
Lennox Primary Career Week
Contributor
4/2017
The Royal Society Engaging with Schools Programme
Participant
2/3/2017
20th Scottish Cardiovascular Forum
Participant
4/2/2017
The Biochemical Society - Engaging with outreach: funding opportunities for schools
Invited speaker
6/1/2017

more professional activities

Projects

AWERB 3Rs grant 2016
Cunningham, Margaret Rose (Co-investigator) Currie, Susan (Principal Investigator)
Period 01-Aug-2016
BPS Vacation Studentship - Investigating biophysical interactions of PAR inhibitors at the cell membrane using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS)
Cunningham, Margaret Rose (Principal Investigator)
Period 26-Jun-2017 - 01-Sep-2017
The role of gelsolin family proteins in GPCR regulation
Cunningham, Margaret Rose (Principal Investigator)
Period 01-Sep-2015 - 01-Jun-2016
A multi-disciplinary approach to thrombin receptor research - A focus on the interrogation of the Proteinase-activated Receptor 4 (PAR4) interactome
Cunningham, Margaret Rose (Principal Investigator)
Period 01-Aug-2016 - 31-Jul-2018
Using proteomics to study novel function-disrupting PAR4 variants harboured in patient cohorts with platelet dysfunction
Cunningham, Margaret Rose (Principal Investigator)
Period 01-Jun-2015 - 29-Feb-2016

more projects

Address

Strathclyde Institute of Pharmacy and Biomedical Sciences
Hamnett Wing John Arbuthnott Building

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