Design, synthesis and characterisation of agonists for collagen receptors

Lead Research Organisation: University of Cambridge
Department Name: Biochemistry

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Publications

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Almquist T (2012) Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

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Brondijk TH (2012) Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex. in Proceedings of the National Academy of Sciences of the United States of America

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Freise C (2009) The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity. in Matrix biology : journal of the International Society for Matrix Biology

 
Description BBSRC Project Grant (MJD)
Amount £10,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description BHF Programme (RWF3)
Amount £664,000 (GBP)
Funding ID RG/09/003/27122 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2014
 
Description BHF Project Grant Scheme (DAS)
Amount £174,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description BHF Project Grant Scheme (SMJ)
Amount £252,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description MRC Research Grant (GEJ)
Amount £350,000 (GBP)
Funding ID G0601378 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2007 
End 03/2010
 
Description Studentship (EH)
Amount £118,000 (GBP)
Funding ID FS/15/20/31335 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Title Collagen mimetic peptides 
Description Libraries of triple-helical collagen-mimetic peptides used to map the binding of proteins (receptors etc) to collagen; the collagen III Toolkit was completed with Wellcome support, but the collagen II Toolkit was entirely MRC supported. Specific ligands for collagen receptors etc derived from the above. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Materials supplied to the platelet community have underpinned research worldwide on platelet activation, and integrin ligands have again found application in several laboratories both in UK and abroad. VWF-specific peptides are being developed for diagnostics. 
 
Title Receptor-specific and Integrin-binding peptides 
Description A short collagenous peptide that binds integrin by virtue of containing a Gxx'GEx'' motif. Industry standard for integrin-binding activity for collagen-binding integrins. Funding allowed us to maintain the supply of Glycoprotein VI-specific peptides and VWF-specific peptides for platelet and haemostasis research. This lab is the gold standard for such reagents. 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Has the potential to support a wide-range of biocompatible materials; to act as a substrate for cell attachment. 
 
Description Alpha11Beta1 
Organisation University of Bergen
Department Department of Biochemistry and Cell Biology
Country Norway 
Sector Academic/University 
PI Contribution Peptides, collagen homology searches, mapping of sites in-house, etc.
Collaborator Contribution Provision of alpha11-bearing cells; insight, suggestion discussion. (Prof Donald Gulberg)
Impact Diversification into non-fibrillar collagens to map sites for the integrin alpha11beta1. No publications as yet. But we expect to complete the project within the timescale of this grant.
 
Description DDRs 
Organisation Imperial College London
Department Department of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We supplied Toolkits to Imperial College, to map DDR2, then DDR1 binding to collagen. We used truncated and substituted peptides to pinpoint critical residues within the DDR2-binding motif, and synthesised a peptide for crystallisation of a DDR2-peptide complex.
Collaborator Contribution Publication; networking
Impact Publications: co-ordinates of complex; DDR2-binding motif patent application.
Start Year 2006
 
Description Fibronectin 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis and mapping of FN binding to collagen fragments. From our side, this arose from observations of indirect but integrin-dependent binding of cells to collagen. Led to link with Prof I. Campbell and Dr John Vakonakis.
Collaborator Contribution Insight into FN-collagen interaction; provision of FN domains for mapping
Impact Publications 19251642, 20739283 Involves mapping of sites and structural studies.
Start Year 2007
 
Description Heparin 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Public 
PI Contribution Synthesis of peptides that bind heparin specifically, based on sequence mapping in collagen V
Collaborator Contribution We synthesised a heparin-binding collagen fragment and shipped to Lyon for functional testing.
Impact Publication 16815843
 
Description Maastricht 
Organisation Maastricht University (UM)
Country Netherlands 
Sector Academic/University 
PI Contribution Provision of peptides; conducting experiments; analysing data. Hosting of students in Cambridge.
Collaborator Contribution Exchange of personnel and ideas; asssitance in design of prototype apparatus.
Impact Publication 18826391 Understanding role of GpVI and alpha2beta1 in supporting platelet adhesion to collagen under flow; development of flow apparatus in Cambridge. Exchange of personnel (Maastricht students visiting Cambridge during masters programme). Development of synthetic surfaces for bed side analysis of haemostasis defect and anti-platelet therapy. Latter under auspices on Standardization Subcommittee of Int Soc on Thrombosis and Haemostasis.
 
Description Nitric Oxide 
Organisation University of Hull
Department Postgraduate Medical Institute Hull
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of peptides for platelet binding assays
Collaborator Contribution Understanding the regulation of platelet receptor affinity.
Impact Publication 18983487
 
Description VWF and LAIR-1 
Organisation University Medical Center Utrecht (UMC)
Country Netherlands 
Sector Academic/University 
PI Contribution Provision of peptides; analysis interpretation of data. Binding interactions with mutant proteins.
Collaborator Contribution Crystallisation of collagen binding proteins in complex with our peptides, or by themselves. Therefore, detailed understanding of how proteins interact with collagen.
Impact Publications; development of VWF-binding peptides as detailed elsewhere. 20007810 19345263 18363567 17403111 16912226
 
Title OSCAR-specific ligands 
Description Motifs within collagen that bind OSCAR and mediate osteoclast differentiation from monocytic cells. 
IP Reference US2012028903   
Protection Patent application published
Year Protection Granted 2012
Licensed Yes
Impact None
 
Title VWF-specific ligands 
Description The VWF-binding site in collagen III was originally protected, but remained unlicensed and lapsed. However, two companies purchased peptides from the group to develop assays for VWF in plasma, an essential part of the diagnosis of non-haemophiliac bleeding disorders. 
IP Reference WO2007052067 
Protection Patent application published
Year Protection Granted 2007
Licensed Yes
Impact PATENT NOT MAINTAINED Looks as though our materials will form the basis of more reproducible and sensitive kits for two major diagnostic companies. World market is currently 10 million tests per annum. Our research will underpin a significant proportion of these.
 
Title VWF-binding peptide 
Description Assay for von Willebrand disease based on ability of our peptide to bind VWF from patient plasma. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Not yet on the market.