Title

CIRCULATING CELLS: The natural sensors of plaque and patient destabilization

Code

2008 T 86

Principal investigator(s)

G. Pasterkamp

Subject

1.40 Biological factors

Sub-theme

UU CH AT Atherosclerosis (cholesterol)

NHF program

Research Programs - Other 2008

Starting date

2009-01-01

End date

2013-12-31
 

Summary

Introduction. Atherosclerotic cardiovascular disease remains the number one killer of the aging population in Western Society. The natural history of the disease is unknown and clinical events may strike without any warning.There have long been efforts to discover new biomarkers and to validate surrogate endpoints to diagnose patients at risk and to test treatment efficacy. The need for more rapid drug development highlights the role that biomarkers may play in 1- identifying patients at risk for primary and secondary manifestations of the disease, 2- stratification of patients to reach individualized therapy and 3- establishing the efficacy of newly developed drugs for managing atherosclerotic disease.
The Circulating Cell. Partners within the consortium have compelling evidence that suggests cross-talk between the diseased vascular tree and subsets of circulating cells. Therefore, this consortium will focus on functional, molecular and structural characteristics of Circulating Cells that may serve as biomarker for initiation and progression of atherosclerotic disease. Moreover it well develop and validate technologies that evaluate these characteristics of Circulating Cells in patients at risk. This approach is innovative since most biomarkers and imaging targets have been searched for in serum, plasma or atherosclerotic plaques. Cohort studies with systematic storage of fractions of Circulating Cells are lacking which further reflects the originality of the proposed approach.

Objective. It is hypothesized that cellular responsiveness of blood cells will function as sensors for plaque and patient destabilization. Objective of this consortium is to develop point-of-care technology that aims to evaluate the characteristics of circulating blood cells in order to asses risk for atherosclerotic disease progression.

Approach. The strategy of the consortium can be summarized as follows:
A-The Clinical Platform delivers patient data and biological samples to the discovery platform. The clinical platform will operate in three phases. In the first phase (Month 1-18) patients will be included, data collected and biological material harvested. In the second phase (Month 12-48) devices originating from the technology platform will be tested on feasibility in patient studies. In the third phase (Month 24-60) new technology will be tested in clinical validation studies.
B- The Discovery platform analyzes samples and data using –omics approaches and state of the art
bioinformatics. This platform will generate cell based biomarkers for atherosclerotic disease.
C- The outcome of the target search will be made available to the Technical Platform. Targets will be provided to the primary deliverable of the consortium: a start up company that will protect target IP. The targets will then be made available to partners operating within the consortium. The technology platform is divided in operational units in which public and private partners work together on dedicated deliverables.
D- Targets, devices and techniques developed in the technical platform require validation. Devices and technological achievements will be tested on application feasibility (phase 2 clinical platform), improved and again validated in the clinical platform (phase 3). The consortium will make use of the infrastructure of three ongoing clinical trials for the purpose of target and device validation. One of these dedicated validation studies includes a cohort with young children at risk, allowing biomarker validation from advanced stages to initiation of disease. The other studies include cohorts that undergo coronary interventions and fractional flow reserve measurements, respectively.

Deliverables. Using state of the art target discovery technologies and bioinformatics in a well defined patient group, newly discovered biomarkers will be applied to develop a protein and genetic fingerprint of the patient at risk. This fingerprint becomes the basis of IP that will be generated by a startup company. These newly discovered targets will be implemented in 9 units where technology development is executed and where 75% of the total budget will be invested. In these technology units new devices will be constructed that identify targets of interest and that will lead to clinically applicable technological approaches to identify the patient at risk. Among these technology developments are a biosensor that will analyse protein and secretome signatures of
circulating cells, dedicated chips revealing expressions of genes that are demonstrated to be expressed in patients at risk, FACS combi-kit with antibody cocktails for fast screening of circulating cells of patients in a clinical setting and a light-electron microscope to search for morphological and co-expression of markers of interest. The outcome will be evaluated using standard operational procedures for medical technology assessments.

Partners. Academic partners with a track record in both physical and medical sciences are involved. Next to global operating industries also 6 Dutch SMEs will participate in this research program. Two SMEs have been initiated in 2007 with biomarker discovery in the field of atherosclerotic disease as a primary core-business.

In summary, Circulating Cells is a research program that will make use of a relatively unexplored source for biomarker discovery and will strongly stimulate technology development and clinical validation of target detection to identify the patients who are at risk for atherosclerotic disease progression.
 

Keywords

atherosclerosis - ischemia - platelets - proteomics
 

Publications

 Title Using meta-regression analyses in addition to conventional systematic review methods to examine the variation in cost-effectiveness results - a case study
 Type International Publication
 Year / Volume / Page 2018:20 :23
 PubMed
 Author(s) L.T. Burgers, F.T. van de Wetering, J. Severens, K. Redekop
 Journal bmc health serv res
 
 Title Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children
 Type International Publication
 Year / Volume / Page 2017:12 :e0187068
 PubMed
 Author(s) G. Keustermans, L.B, van der Heijden, B. Boer, R. Scholman, R. Nuboer, G. Pasterkamp, B.J. Prakken, W. de Jager, E. Kalkhoven, A.J. Janse, H.S. Schipper
 Journal plos one
 
 Title Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults
 Type International Publication
 Year / Volume / Page 2017:7 :16826
 PubMed
 Author(s) G. Keustermans, D. Kofink, A.L.M. Eikendal, W. de Jager, J. Meerding, R. Nuboer, J.L. Waltenberger, A.O. Kraaijeveld, J.W. Jukema, J.W. Sels, J. Garssen, B.J. Prakken, F.W. Asselbergs, E. Kalkhoven, I.E. Höfer, G. Pasterkamp, H.S. Schipper
 Journal sci rep
 
 Title The effect of P2Y12 inhibition on platelet activation assessed with aggregation- and flow cytometry-based assays
 Type International Publication
 Year / Volume / Page 2017:28 :567-575
 PubMed
 Author(s) T.C. Leunissen, P.P. Wisman, T.C. van Holten, PH.G. de Groot, S.J.A. Korporaal, C.A. Koekman, F.L. Moll, M. Teraa, M.C. Verhaar, G.J. de Borst, R.T. Urbanus, M. Roest
 Journal platelets
 
 Title Platelet density per monocyte predicts adverse events in patients after percutaneous coronary intervention
 Type International Publication
 Year / Volume / Page 2016:115 :353-360
 PubMed
 Author(s) B. Rutten, M. Roest, E.A. McClellan, J.W. Sels, A.P. Stubbs, J.W. Jukema, P.A.F.M. Doevendans, J.L. Waltenberger, A.J. van Zonneveld, G. Pasterkamp, PH.G. de Groot, I.E. Höfer
 Journal thromb haemost
 
 Title Treatment variation in stent choice in patients with stable or unstable coronary artery disease
 Type International Publication
 Year / Volume / Page 2016:24 :110-119
 PubMed
 Author(s) L.T. Burgers, E.A. McClellan, I.E. Höfer, G. Pasterkamp, J.W. Jukema, S. Horsman, N.H.J. Pijls, J.L. Waltenberger, M.A. Hillaert, A.P. Stubbs, J. Severens
 Journal neth heart j
 
 Title Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses
 Type International Publication
 Year / Volume / Page 2015:22 :e62080
 PubMed
 Author(s) T.C. van Holten, L.F. Waanders, PH.G. de Groot, J. Vissers, I.E. Höfer, G. Pasterkamp, M.W.J. Prins, M. Roest
 Journal plos one
 
 Title Circulating cells as biomarkers in cardiovascular disease -The difference between men and women-
 Type PhD Thesis
 Year 2015
 Author(s) T.J. Zweers
 ISBN 9789462039582
 University Universiteit Leiden
 Promotion date 2015-12-22
 
 Title Microfluidic devices for mechanical characterization and manipulation of monocytes
 Type PhD Thesis
 Year 2015
 Author(s) A. Ravetto
 ISBN 9789038638126
 University Technische Universiteit Eindhoven
 Promotion date 2015-04-07
 
 Title FLow-induced PRotrusions (FLIPRs): a platelet-derived platform for the retrieval of microparticles by monocytes and neutrophils
 Type International Publication
 Year / Volume / Page 2014:114 :780-791
 PubMed
 Author(s) C. Tersteeg, H.F.G. Heijnen, A. Eckly, G. Pasterkamp, R.T. Urbanus, C. Maas, I.E. Höfer, R. Nieuwland, R.W. Farndale, C. Gachet, PH.G. de Groot, M. Roest
 Journal circ res
 
 Title Increased platelet reactivity is associated with circulating platelet-monocyte complexes and macrophages in human atherosclerotic plaques
 Type International Publication
 Year / Volume / Page 2014:14 :e105019
 PubMed
 Author(s) B. Rutten, C. Tersteeg, J.E.P. Vrijenhoek, T.C. van Holten, E.H.A.M. Elsenberg, E.M. Mak-Nienhuis, G.J. de Borst, J.W. Jukema, N.H.J. Pijls, J.L. Waltenberger, A.J. van Zonneveld, F.L. Moll, E.A. McClellan, A.P. Stubbs, G. Pasterkamp, I.E. Höfer, PH.G. de Groot, M. Roest
 Journal plos one
 
 Title Local plaque characteristics and circulating cells in atherosclerosis. The ATHERO-EXPRESS biobank
 Type PhD Thesis
 Year 2014
 Author(s) V.P.W. Scholtes
 ISBN 9789461086778
 University Universiteit Utrecht
 Promotion date 2014-05-27
 
 Title Monocytic cells become less compressible but more deformable upon activation
 Type International Publication
 Year / Volume / Page 2014:9 :e92814
 PubMed
 Author(s) A. Ravetto, H.M. Wyss, P.D. Anderson, J.M.J. den Toonder, C.V.C. Bouten
 Journal plos one
 
 Title Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy
 Type International Publication
 Year / Volume / Page 2014:129 :1320-1331
 PubMed
 Author(s) C. Tersteeg, S. de Maat, S.F. de Meyer, M.W.J. Smeets, A.D. Barendrecht, M. Roest, G. Pasterkamp, R. Fijnheer, K. Vanhoorelbeke, PH.G. de Groot, C. Maas
 Journal circulation
 
 Title Quantification of platelet-surface interactions in real-time using intracellular calcium signaling
 Type International Publication
 Year / Volume / Page 2014:16 :217-227
 PubMed
 Author(s) H.M. van Zijp, A.D. Barendrecht, J. Riegman, J.H.M. Goudsmits, A.M. de Jong, H. Kress, M.W.J. Prins
 Journal biomed microdevices
 
 Title Quantitative proteomics analysis reveals similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets
 Type International Publication
 Year / Volume / Page 2014:103 :140-146
 PubMed
 Author(s) T.C. van Holten, O.B. Bleijerveld, P. Wijten, PH.G. de Groot, A.J.R. Heck, A.D. Barendrecht, T.H. Merkx, A. Scholten, M. Roest
 Journal cardiovasc res
 
 Title The Relationship between Fractional Flow Reserve, Platelet Reactivity and Platelet Leukocyte Complexes in Stable Coronary Artery Disease
 Type International Publication
 Year / Volume / Page 2014:8 :e83198
 PubMed
 Author(s) J.W. Sels, B. Rutten, T.C. van Holten, M.A. Hillaert, J.L. Waltenberger, N.H.J. Pijls, G. Pasterkamp, PH.G. de Groot, M. Roest
 Journal plos one
 
 Title Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease
 Type International Publication
 Year / Volume / Page 2013:34 :3451-3457
 PubMed
 Author(s) H.C. de Boer, C. van Solingen, J. Prins, J.M.G.J. Duijs, M.V. Huisman, T.J. Rabelink, A.J. van Zonneveld
 Journal eur heart j
 
 Title Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study
 Type International Publication
 Year / Volume / Page 2013:102 :847-856
 PubMed
 Author(s) I.E. Höfer, J.W. Sels, J.W. Jukema, S. Bergheanu, E.A.L. Biessen, E.A. McClellan, M.J.A.P. Daemen, P.A.F.M. Doevendans, PH.G. de Groot, M.A. Hillaert, S. Horsman, M. Ilhan, J. Kuiper, N.H.J. Pijls, K. Redekop, P.J. van der Spek, A.P. Stubbs, E. van de Veer, J.L. Waltenberger, A.J. van Zonneveld, G. Pasterkamp
 Journal clin res cardiol
 
 Title High Precision Platelet Releasate Definition by Quantitative Reversed Protein Profiling--Brief Report
 Type International Publication
 Year / Volume / Page 2013:33 :1635-1638
 PubMed
 Author(s) P. Wijten, T.C. van Holten, L.L. Woo, O.B. Bleijerveld, M. Roest, A.J.R. Heck, A. Scholten
 Journal arterioscler thromb vasc biol
 
 Title On platelet biology and cardiovascular disease
 Type PhD Thesis
 Year 2013
 Author(s) T.C. van Holten
 ISBN 9789088916403
 University Universiteit Utrecht
 Promotion date 2013-06-20
 
 Title Platelets in atherothrombosis
 Type PhD Thesis
 Year 2013
 Author(s) C. Tersteeg
 ISBN 9789088916465
 University Universiteit Utrecht
 Promotion date 2013-05-15
 
 Title Targeted phosphotyrosine profiling of glycoprotein VI signaling implicates oligophrenin-1 in platelet filopodia formation
 Type International Publication
 Year / Volume / Page 2013:33 :1538-1543
 PubMed
 Author(s) O.B. Bleijerveld, T.C. van Holten, C. Preisinger, J.J. van der Smagt, R.W. Farndale, T. Kleefstra, M.H. Willemsen, R.T. Urbanus, PH.G. de Groot, A.J.R. Heck, M. Roest, A. Scholten
 Journal arterioscler thromb vasc biol
 
 Title The influence of inhomogeneous adhesion on the detachment dynamics of adhering cells
 Type International Publication
 Year / Volume / Page 2013:42 :419-426
 PubMed
 Author(s) M. Irmscher, K.A. van Laarhoven, A.M. de Jong, M.W.J. Prins
 Journal eur biophys j
 
 Title Toll-Like Receptor induced CD11b and L-selectin response in patients with coronary artery disease
 Type International Publication
 Year / Volume / Page 2013:8 :e60467
 PubMed
 Author(s) E.H.A.M. Elsenberg, M.A. Hillaert, H.M. den Ruijter, J.W. Sels, V.P.W. Scholtes, H.M. Nathoe, J. Kuiper, J.W. Jukema, P.A.F.M. Doevendans, G. Pasterkamp, I.E. Höfer
 Journal plos one
 
 Title Toll-like receptor response and circulating cells in cardiovascular disease
 Type PhD Thesis
 Year 2013
 Author(s) E.H.A.M. Elsenberg
 ISBN 9789088917189
 University Universiteit Utrecht
 Promotion date 2013-11-08
 
 Title A fibronectin-fibrinogen-tropoelastin coating reduces smooth muscle cell growth but improves endothelial cell function
 Type International Publication
 Year / Volume / Page 2012:16 :2117-2126
 PubMed
 Author(s) C. Tersteeg, M. Roest, E.M. Mak-Nienhuis, E. Ligtenberg, I.E. Höfer, PH.G. de Groot, G. Pasterkamp
 Journal j cell mol med
 
 Title Deep proteome profiling of circulating granulocytes reveals bactericidal/permeability-increasing protein as a biomarker for severe atherosclerotic coronary stenosis
 Type International Publication
 Year / Volume / Page 2012:11 :5235-5244
 PubMed
 Author(s) O.B. Bleijerveld, P. Wijten, S. Cappadona, E.A. McClellan, A.N. Polat, R. Raijmakers, J.W. Sels, L. Colle, S. Grasso, H.W. van den Toorn, B. van Breukelen, A.P. Stubbs, G. Pasterkamp, A.J.R. Heck, I.E. Höfer, A. Scholten
 Journal j proteome res
 
 Title Fractional flow reserve is not associated with inflammatory markers in patients with stable coronary artery disease
 Type International Publication
 Year / Volume / Page 2012:7 :e46356
 PubMed
 Author(s) J.W. Sels, E.H.A.M. Elsenberg, I.E. Höfer, A.J. van Zonneveld, J. Kuiper, J.W. Jukema, N.H.J. Pijls, G. Pasterkamp
 Journal plos one
 
 Title Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response
 Type International Publication
 Year / Volume / Page 2012:122 :527-533
 PubMed
 Author(s) E.H.A.M. Elsenberg, D. Versteeg, J.W. Sels, P.J.J. Vlaar, M.G. Hobbelink, M.J.M. Cramer, D.P.V. de Kleijn, R.A. Tio, B.J.G.L. de Smet, P.A.F.M. Doevendans, I.E. Höfer, G. Pasterkamp
 Journal clin sci
 
 Title Measurement of platelet responsiveness using antibody-coated magnetic beads for lab-on-a-chip applications
 Type International Publication
 Year / Volume / Page 2012:23 :626-632
 PubMed
 Author(s) H.M. van Zijp, C.C.M.M. Schot, A.M. de Jong, N. Jongmans, T.C. van Holten, M. Roest, M.W.J. Prins
 Journal platelets
 
 Title Probing the cell membrane by magnetic particle actuation and Euler angle tracking
 Type International Publication
 Year / Volume / Page 2012:102 :698-708
 PubMed
 Author(s) M. Irmscher, A.M. de Jong, H. Kress, M.W.J. Prins
 Journal biophys j
 
 Title Systemic inflammation in childhood obesity: circulating inflammatory mediators and activated CD14++ monocytes
 Type International Publication
 Year / Volume / Page 2012:55 :2800-2810
 PubMed
 Author(s) H.S. Schipper, R. Nuboer, S. Prop, H.J. van den Ham, F.K. de Boer, C. Kesmir, I.M.H. Mombers, K.A. van Bekkum, J. Woudstra, J.H. Kieft, I.E. Höfer, W. de Jager, B.J. Prakken, M.J.H. van Summeren, E. Kalkhoven
 Journal diabetologia
 
 Title Collagen stimulation of platelets induces a rapid spatial response of cAMP and cGMP signaling scaffolds
 Type International Publication
 Year / Volume / Page 2011:7 :2311-2319
 PubMed
 Author(s) L. Margarucci, M. Roest, C. Preisinger, O.B. Bleijerveld, T.C. van Holten, A.J.R. Heck, A. Scholten
 Journal mol biosyst
 
 Title Improved peptide identification by targeted fragmentation using CID, HCD and ETD on an LTQ-Orbitrap Velos
 Type International Publication
 Year / Volume / Page 2011:6 :2377-2388
 PubMed
 Author(s) C.K. Frese, A.F.M. Altelaar, M.L. Hennrich, D. Nolting, M. Zeller, J. Griep-Raming, A.J.R. Heck, S. Mohammed
 Journal j proteome res
 
 Title Improving SRM assay development: a global comparison between triple quadrupole, ion trap, and higher energy CID peptide fragmentation spectra
 Type International Publication
 Year / Volume / Page 2011:10 :4334-4341
 PubMed
 Author(s) E.L. de Graaf, A.F.M. Altelaar, B. van Breukelen, S. Mohammed, A.J.R. Heck
 Journal j proteome res
 
 Title Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis
 Type International Publication
 Year / Volume / Page 2011:121 :205-214
 PubMed
 Author(s) V.P.W. Scholtes, D. Versteeg, J.P.P.M. de Vries, I.E. Höfer, A.H. Schoneveld, P.R.S. Stella, P.A.F.M. Doevendans, J.K. van Keulen, D.P.V. de Kleijn, F.L. Moll, G. Pasterkamp
 Journal clin sci
 
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