Lecturer in Veterinary Anatomy, Fellow and
College Lecturer in Pharmacology, Selwyn College
Tel: +44 (0)1223 333745, Fax: +44 (0)1223 333840, E-mail: email@example.com
I qualified as a vet in 1992 having studied Pharmacology and Clinical Veterinary Medicine at Queens' College, Cambridge and the Cambridge Veterinary School. After completing a PhD in platelet pharmacology at the Department of Veterinary Medicine, Cambridge, I moved into industry and worked for four years at AstraZeneca in Loughborough. In 2000, I returned to academia in the Department of Pharmacology, Oxford and subsequently moved to the Department of Biochemistry, Cambridge in 2003. In 2007 I was elected as a Fellow of Selwyn College. From 2010 I was a Lecturer in Pharmacology in the School of Pharmacy, Queen’s University Belfast and returned to Cambridge, to the Department of Physiology, Development and Neuroscience, and to Selwyn College in April 2012.
I currently supervise pharmacology (aka MoDA) and have done so for a long list of colleges since 1989. Former supervisees have gone on to become University Lecturers, Government Ministers and some of them are still medics and vets! In PDN, I teach and examine veterinary anatomy.
I am interested in the pharmacology of drugs which activate and inhibit platelets, and in the interaction of proteins and receptors with collagen. The connection is that collagen is a potent activator of platelets and plays a key role in the initiation of haemostasis and thrombosis. I also have a longstanding interest in modelling and statistical methods for analysing pharmacological and other biological data.
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In the lab we measure platelet functions including aggregation, release of adenine nucleotides using analytical HPLC, adhesion of platelets to various ligands including fibrinogen and collagen, intracellular signalling using Western Blotting techniques and intracellular calcium signalling (in collaboration with Dr Stewart Sage).
I previously worked on anti-platelet drug development and was part of the team at AstraZeneca which identified and developed the P2Y12 antagonists drug ticagrelor (now marketed as Brilique® for the prevention of arterial thrombosis) and cangrelor (which has recently seen positive results from a Phase III clinical trials!).
Current projects involve the investigation of the effect on platelets of anti-depressant drugs, BcL-2 inhibitors and, in collaboration with Dr Tai-Ping Fan (Department of Pharmacology), compounds derived from traditional Chinese remedies.
Protein-collagen interactions Keratinocyte growth factor (KGF, also known as Fibroblast Growth Factor-7) is important in maintaining the integrity and health of epithelial membranes. It is synthesised and secreted by mesenchymal cells and diffuses through the extracellular matrix to act on epithelial cells to promote growth. A recombinant preparation of human KGF called palifermin is sold as Kepivance® and used to treat oral mucositis in patients undergoing chemo- and radiotherapy.
It has previously been reported that KGF binds to collagen (Ruehl et al., 2002). Our preliminary data with palifermin (generously provided by Swedish Orphan Biovitrum) confirms this observation. In collaboration with Prof Richard Farndale (Department of Biochemistry, Cambridge) we are seeking to identify the binding motifs present in collagen which support the interaction.
We are also developing methods for the expression of KGF in E. coli. This will enable us to modify the structure of KGF and identify binding epitopes in the protein.
Data modelling and analysis I have developed modelling and statistical solutions for diverse projects, including the determination of changes in fish populations in the Seychelles (Spalding & Jarvis, 2002), analysis of mutant peas (Ashby et al., 2011), determination of binding sites in 5-HT3 channels (Thompson et al., 2011) and the analysis of multiple interactions with collagen peptides (Raynal et al., 2006). I also lecture on statistics and experimental design for the Home Office Module 5 course in Cambridge.
Phi-macology? In collaboration with Dr Andrew Thompson (Department of Biochemistry, Cambridge), I have recently described a simple analytical test to distinguish between channel blocking drugs which bind at the same and different binding sites within ion channels. This study revealed an unexpected role for the Golden Ratio (also known as phi f) in the design and analysis of drug combination experiments and has just been published by Trends in Pharmacological Sciences. This piece was covered by a news article on ChemistryWorld.
Population Pharmacometrics. I also use Non-linear Mixed Effects Modelling on in vitro pharmacological data and in particular, data from animal experiments. This analysis enables multiple sources of variability to be modelled and quantified. This can be advantageous when there is significant variability between experiments as is often the case with biological assays and in vivo studies in particular. Efficient experimental design and analysis can result in more accurate results and in using fewer animals in accordance with the 3Rs "reduction" principle. This can be done using Excel and for more complex data sets with NONMEM®.
Current lab members
Alice Watson (BBSRC Research Experience Placement, Summer 2013)
Nader Habib Bedwani (Summer project student, 2013)
Previous lab members
Ruoling Yan (Part II student, PDN 2012-13)
Nader Habib Bedwani (Part II student, PDN 2012-13)
Nathan Hudson-Peacock (Part II student, Pharmacology 2013)
Dr Stewart Sage (PDN)
Dr Mike Mason (PDN)
Prof Richard Farndale (Department of Biochemistry, Cambridge)
Dr Tai-Ping Fan (Department of Pharmacology, Cambridge)
Dr Penny Watson (Department of Veterinary Medicine, Cambridge)
Dr Andrew Thompson (Department of Biochemistry, Cambridge)
Prof Chris Scott (School of Pharmacy, Queen’s University Belfast)
Funding: Marmaduke Sheild Fund (2013), BBSRC (Research Experience Placement 2013), Royal Society (2011-12).
Above: KGF binds to the triple-helical domain of collagen. The details of the interaction are unknown. The image shows the results of in silico docking of human KGF and a synthetic collagen peptide. The objective of the project is to identify the sequence within collagen that is responsible for supporting KGF binding.