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Dr Gavin Jarvis

I conduct research into the pharmacology of drugs that activate and inhibit platelets. I am also interested 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 an interest in data modelling and statistical methods for analysing pharmacological and other biological problems.
Dr Gavin Jarvis

Lecturer in Veterinary Anatomy

Fellow, Graduate Tutor and College Lecturer in Pharmacology, Selwyn College


Office Phone: +44 (0) 1223 333745, Fax: +44 (0) 1223 333840

Research Interests

Platelet Pharmacology and Drug Discovery

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 and BcL-2 inhibitors.

We are also exploring the potential for using ‘big data’ to predict previously unrecognised anti-platelet activity in known drugs. This project has been conducted in collaboration with Dr Paul Schofield.

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.

Quantification of Natural Human Embryo Mortality

The rate of early human embryo mortality and pregnancy loss is a topic of perennial interest to many people. However, it is surprisingly uncertain how many human embryos perish under natural circumstances. I have conducted a comprehensive review and re-analysis of available data from studies that have addressed this difficult problem. These studies have recently been published in the Open Science publishing platform, F1000Research.

Data Modelling and Statistical 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 Project Licence course in Cambridge and for the Part II Pharmacology course. I am the pre-clinical methodological reviewer for Research and Practice in Thrombosis & Haemostasis.

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®.

Funding: British Heart Foundation (2014-17); BSHT (2016); Marmaduke Sheild Fund (2013); BBSRC (Research Experience Placement 2013), Royal Society (2011-12).

Current lab members
Harvey Roweth (BHF PhD Fellowship) The effects of selective serotonin reuptake inhibitors on platelets.

Former lab members
Hector Newman (Clare, Part II Pharmacology, 2017)
Osama Elhakeem (Selwyn, BSHT Summer Programme, 2016)
Sara Devereux (Trinity, Part II Pharmacology, 2016)
Alex Evans (Christ’s, Part II Pharmacology, 2016)
Hannah Rhodes-Cheong (Sidney Sussex, Part II PDN, 2015-16)
Bethany Campbell (Newnham, Summer Student, 2015)
Roma McCluskey (Downing, Part II Pharmacology, 2015)
Nicole Fowler (Newnham, Part II PDN, 2014-15)
Cai Read (Jesus, Part II Pharmacology, 2014)
Alisha Chauhan (Christ’s, Part II PDN, 2013-14)
Alice Watson (Fitzwilliam, BBSRC Research Experience Placement, Summer 2013, Part II PDN 2013-14)
Nathan Hudson-Peacock (Christ’s, Part II Pharmacology, 2013)
Nader Habib Bedwani (Christ’s, Part II PDN, 2012-13; Summer project student, 2013)
Ruoling Yan (Part II PDN, 2012-13)

Collaborators
Dr Stewart Sage (PDN)
Dr Paul Schofield (PDN)
Prof Richard Farndale (Department of Biochemistry, Cambridge)
Dr Penny Watson (Department of Veterinary Medicine, Cambridge)

Teaching

Part IA MVST Veterinary Anatomy and Physiology; Homeostasis

Part IB MVST Mechanisms of Drug Action; Human Reproduction

Part II Pharmacology Statistics and Pharmacological Data Analysis

Key Publications

Jarvis GE. Early embryo mortality in natural human reproduction: What the data say, F1000Res. 2017; 5:2765. (doi: 10.12688/f1000research.8937.2)

Jarvis GE. Estimating limits for natural human embryo mortality, F1000Res. 2016; 5:2083. (doi: 10.12688/f1000research.9479.2)

Jarvis GE, Barbosa R, Thompson AJ. Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling, J Pharmacol Exp Ther. 2016; 356(3):549-62.

Antonio LS, Jeggle P, MacVinish LJ, Bartram JC, Miller H, Jarvis GE, Levy FM, Santesso MR, Leite AL, Oliveira RC, Buzalaf MA, Edwardson JM. The effect of fluoride on the structure, function, and proteome of a renal epithelial cell monolayer, Environ Toxicol. 2017; 32(4):1455-67.

Sim FC, Angadi D, Jarvis GE, Porteous M. Assessing clarity and erasability of commercially available pens for surgical site marking: a comparative study in human volunteers, J Pharmacol Exp Ther. 2016; 356(3):549-62.

Reihill JA, Moreland M, Jarvis GE, McDowell A, Einarsson GG, Elborn JS, Martin SL. Bacterial proteases and haemostasis dysregulation in the CF lung, J Cyst Fibros. 2017; 16(1):49-57.

Schmid D, Jarvis GE, Fay F, Small DM, Greene MK, Majkut J, Spence S, McLaughlin KM, McCloskey KD, Johnston PG, Kissenpfennig A, Longley DB, Scott CJ. Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity, Cell Death Dis. 2014; 5:e1454.

Jarvis GE, Thompson AJ. A Golden Approach to Ion Channel Inhibition, Trends in Pharm Sci. 2013; 34(9):481-8.

Sage SO, Jarvis GE, Jardín I, Rosado JA, Harper AG. The TRPV1 ion channel is expressed in human but not mouse platelets, Platelets. 2014; 25(5):390-2.

Slatter DA, Bihan DG, Jarvis GE, Stone R, Pugh N, Giddu S, Farndale RW, (2012), The properties conferred upon triple-helical collagen-mimetic peptides by the presence of cysteine residues, Peptides, 2012;36:86-93 (PMID: 22555281)

Pugh N, Jarvis GE, Koch A, Sakariassen KS, Davis B, Farndale RW, (2012), The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface, J Thromb Thrombolysis, 33:6-15

Jarvis GE, Bihan D, Hamaia S, Pugh N, Ghevaert CJ, Pearce AC, Hughes CE, Watson SP, Ware J, Rudd CE, Farndale RW, (2012), A role for adhesion and degranulation-promoting adapter protein in collagen-induced platelet activation mediated via integrin α2β1, J Thromb Haemost, 10:268-77

Kulkarni S, Sitaru C, Jakus Z, Anderson KE, Damoulakis G, Davidson K, Hirose M, Juss J, Oxley D, Chessa TA, Ramadani F, Guillou H, Segonds-Pichon A, Fritsch A, Jarvis GE, Okkenhaug K, Ludwig R, Zillikens D, Mocsai A, Vanhaesebroeck B, Stephens LR, Hawkins PT, (2011), PI3Kβ plays a critical role in neutrophil activation by immune complexes, Sci Signal, 4:ra23

Ashby JA, Stevenson CE, Jarvis GE, Lawson DM, Maule AJ, (2011), Structure-based mutational analysis of eIF4E in relation to sbm1 resistance to pea seed-borne mosaic virus in pea, PLoS One, 6:e15873

Thompson AJ, Jarvis GE, Duke RK, Johnston GA, Lummis SC, (2011), Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site, Neuropharmacology, 60:488-95

Anderson KE, Boyle KB, Davidson K, Chessa TA, Kulkarni S, Jarvis GE, Sindrilaru A, Scharffetter-Kochanek K, Rausch O, Stephens LR, Hawkins PT, (2008), CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of Escherichia coli or Staphylococcus aureus is regulated by class III but not class I or II PI3Ks, Blood, 112:5202-11

Farndale RW, Lisman T, Bihan D, Hamaia S, Smerling CS, Pugh N, Konitsiotis A, Leitinger B, de Groot PG, Jarvis GE, Raynal N, (2008), Cell-collagen interactions: the use of peptide Toolkits to investigate collagen-receptor interactions, Biochem Soc Trans, 36:241-50

Guerrero JA, Shafirstein G, Russell S, Varughese KI, Kanaji T, Liu J, Gartner TK, Bäumler W, Jarvis GE, Ware J, (2008), In vivo relevance for platelet glycoprotein Ibα residue Tyr276 in thrombus formation, J Thromb Haemost, 6:684-91 

Jarvis GE, Raynal N, Langford JP, Onley DJ, Andrews A, Smethurst PA, Farndale RW, (2008), Identification of a major GpVI-binding locus in human type III collagen, Blood, 111:4986-96 

Farndale RW, Slatter DA, Siljander PR, Jarvis GE, (2007), Platelet receptor recognition and cross-talk in collagen-induced activation of platelets, J Thromb Haemost, 5(Suppl 1):220-9

Smethurst PA, Onley DJ, Jarvis GE, O'Connor MN, Knight CG, Herr AB, Ouwehand WH, Farndale RW, (2007), Structural basis for the platelet-collagen interaction: the smallest motif within collagen that recognizes and activates platelet Glycoprotein VI contains two glycine-proline-hydroxyproline triplets, J Biol Chem, 282:1296-304

Raynal N, Hamaia SW, Siljander PR, Maddox B, Peachey AR, Fernandez R, Foley LJ, Slatter DA, Jarvis GE, Farndale RW, (2006), Use of synthetic peptides to locate novel integrin α2β1-binding motifs in human collagen III, J Biol Chem, 17;281(7):3821-31

Jarvis GE, Best D, Watson SP, (2004), Differential roles of integrins α2β1 and αIIbβ3 in collagen and CRP-induced platelet activation, Platelets ,15:303-13

Jarvis GE, Best D, Watson SP, (2004), Glycoprotein VI/Fc receptor gamma chain-independent tyrosine phosphorylation and activation of murine platelets by collagen, Biochem J, 383:581-8

Jarvis GE, (2004), Platelet aggregation in whole blood: impedance and particle counting methods, Methods Mol Biol, 272:77-87

Jarvis GE, (2004), Platelet aggregation: turbidimetric measurements, Methods Mol Biol, 272:65-76

Spalding MD, Jarvis GE, (2002), The impact of the 1998 coral mortality on reef fish communities in the Seychelles, Mar Pollut Bull, 44:309-21

Jarvis GE, Humphries RG, Robertson MJ, Leff P, (2000), ADP can induce aggregation of human platelets via both P2Y1 and P2T receptors, Br J Pharmacol, 129:275-82

 

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.