EuCAR
Euregio Cardiovascular International Research Training Group GRK 1508 (EuCAR) ‘Arterial Remodeling ’
RWTH Aachen University – Maastricht University
Spokesman: Prof. Dr. med. Christian Weber Institute for Molecular Cardiovascular Research (IMCAR) Co-Spokesman: Prof. Mat Daemen, MD/PhD Cardiovascular Research Institute Maastricht (CARIM) GRK 1508 From common scientific profiles towards an EuCAR integrated model for a European University Hospital
Research & Teaching Medizin & Clinical Services & Technik
EuCAR
Klinische Kardio- Medizinische Fakultät Neuro- vaskuläre wissen- Forschung schaften
Statement of the state minister for Innovation, Science, Research and Technology of NRW (03/2007) concerning University Medicine and Medical Research: Entzündung - University Hospitals RWTH Aachen – Maastricht & Folgen - integration of clinical, research and teaching activities - cooperation for future developments and shared structures - aiming at a the first ‘European University Hospital ’ GRK 1508 From common scientific profiles towards an EuCAR integrated model for a European University Hospital
Research & Teaching Medizin & Clinical Services & Technik
EuCAR
Klinische Kardio- Medizinische Fakultät Neuro- vaskuläre wissen- Forschung 29 km schaften
Statement of the state minister for Innovation, Science, Research and Technology of NRW (03/2007) concerning University Medicine and Medical Research: Entzündung - University Hospitals RWTH Aachen – Maastricht & Folgen - integration of clinical, research and teaching activities - cooperation for future developments and shared structures - aiming at a the first ‘European University Hospital ’ GRK 1508 Strategic Alliance and Complementarity EuCAR of UKA - RWTH and azM - University Maastricht
UKA – RWTH azM – UM CV focus - IMCAR CVC - CARIM
Inflammation & Atherogenesis Plaque Instability & Thrombosis
Stents & Tissue Engineering Cardiac Failure & Atrial Fibrillation
Transgenics & Biomaterials Metabolic Aspects & Molecular Imaging
Growth Clinical Imaging & Clinical Hemostasis, Areas: Intervention (W3) Diabetes & HF
Transgenic Service Radiochemistry
Structural Biology Peptide Synthesis
Joint Vascular Surgery / European Vascular Centre Areas: Biophysics - Live Microscopy (W2), IMCAR - CARIM ( Weber )
Pediatric Cardiology (W3)
Future options: Radiology & CTMM GRK 1508 Participating Applicants and Institutions EuCAR (SC – member steering committee)
RWTH Aachen University University of Maastricht Univ.-Prof. Dr. Christian Weber ( SC ) Prof. Dr. Mat Daemen (SC ) Institute for Molecular Cardiovascular Research (IMCAR) Cardiovascular Research Institute Maastricht Univ.-Prof. Dr. Jürgen Bernhagen ( SC ) Prof. Dr. Erik Biessen Department of Biochemistry CARIM, Pathology Univ.-Prof. Dr. Jürgen Floege ( SC ) Prof. Dr. Wim Buurman ( SC ) Medical Clinic II (Nephrology) NUTRIM, Surgery Univ.-Prof. Dr. Willi Jahnen-Dechent Prof. Dr. Menno de Winther Institute for Biomedical Technology - Biomaterials CARIM, Molecular Genetics Univ.-Prof. Dr. Malte Kelm Prof. Dr. Tilman Hackeng (SC ) Medical Clinic I (Cardiology/Angiology) CARIM, Biochemistry Priv.-Doz. Dr. Andreas Ludwig Prof. Dr. Johan Heemskerk IMCAR - Division of Cardiovascular Biochemistry CARIM, Biochemistry Univ.-Prof. Dr. Thomas Schmitz-Rode Prof. Dr. Michael Jacobs Institute for Biomedical Technology – Technology Department of Vascular Surgery Univ.-Prof. Dr. Christian Trautwein Prof. Dr. Marc Post Medical Clinic III (Gastroenterology) CARIM, Physiology / Biophysics Univ.-Prof. Dr. Stefan Uhlig Prof. Dr. Cees Vermeer Institute for Pharmacology CARIM, Biochemistry Univ.-Prof. Dr. Martin Zenke Prof. Dr. Johannes Waltenberger Institute for Biomedical Technology – Cell Biology Department of Cardiology GRK 1508 Arterial Remodeling during Atherosclerosis EuCAR
Endothelial Formation of dysfunction: fatty-streak monocyte lesions adhesion
Fibro- Unstable proliferative plaque: growth rupture & thrombosis
R. Ross, P. Libby G. Hansson
R. Virchow ( Endarteritis chronica deformans ): ‘Atherosclerosis is caused by plasma components (including lipids) eliciting an inflammatory response in the arterial wall.‘ GRK 1508 Balance of immune cell regulation EuCAR in inflammatory plaques
pro-inflammatory: anti-inflammatory:
Th1-cells regulatory T cells IFN-γ IL-10 IL-12 TGF-β IL-18 Th2-cells? IL-4 IL-5 CD40/CD40L IL-4? dendritic cells?
MCP-1 RANTES MIF Hansson, NEJM (2005) Tedgui & Mallat, Phys. Rev. (2006) GRK 1508 Inspiration by closely related subdisciplines EuCAR
- EPCs, growth factors - IKK and signaling - Platelet microparticles - Arteriogenesis Vascular Biology
- Mast cells - Gene profiling - Costimulatory CD40L Immuno- Arterial - 2-photon microscopy Techno- - Monocyte subsets logy Remodeling - Sheddom proteomics - Complement logy - Tissue engineering
Clinical Translation
- Cardio-/Nephrology - Matrix calcification - Arterial grafts in uremia - Nitrite & cytoprotection GRK 1508 EuCAR: Bilateral Research & Teaching EuCAR
14 Research Projects Education/Training
Aachen Maastricht Aachen Maastricht
Applicants Applicants Professors Professors Lecture Series Master Classes Thesis Committees
MD/PhD program PhD program Tenure-track Tenure-track RWTH Aachen CARIM Maastricht “Mittelbau“ Assistants EuCAR program
Graduate Events Progress Reports Graduate Students (PhD, MD/PhD) Method Modules Annual Workshop
10/08 6 graduates Additional Measures: eLearning EVGN 10/08 2 qualifying • Pregraduate students Platform, CDS Summer Schools 04/09 4 graduates • Qualifying scholarships 10/09 4 graduates • Guest scientists GRK 1508 EuCAR Training and Teaching Activities EuCAR Credit Point System
Credit point system EuCAR requires 100 hours of teaching activities per year equivalent to 100 points 2 points: Participation in lectures, seminars, progress reports, soft skills & regular activities of PhD program Maastricht, MD/PhD program Aachen and EuCAR-specific program 6 points: Participation in obligatory 1-day method seminar modules (individual thesis plan) 5 points: Presentations at national meetings 10 points: Presentation at international meetings Participation in the Annual EuCAR Meeting/Workshop 30% of credit points need to be collected by cross-border activities 18% of activities are obligatory Publications Successful graduates will have 2 publications as a first author with an average impact factor >50% above the subject category (cardiovascular system), i.e. > 3.25 Dutch-German Double Degree: PhD from Maastricht University, Dr. rer.nat. from RWTH Aachen University GRK 1508 Scientific Environment: DFG Program Project Grant FOR809 EuCAR Chemokines and adhesion molecules in cardiovascular pathogenesis
CXCL16 metalloproteases CX3CL1 TP5 CXCR6 TP1 CX3CR1 TP4 TP7 TP2 EPC NO monocyte reperfusion/ JAB SPC SDF-1 CD74 RANTES CXCR4 ery infarct CXCR2 PF4 platelets CCR1/2/5 MIF JAM-A EC LFA1 JAM-A SMC JAB TP6 TP3 macrophage CCL17 Molecular Genetics CCR4 Transgenic Mice DC ZP T-cell
Spokesman: Prof. Dr. Christian Weber Nat Med (2003/2003/2007); Nat Immunol (2002/2006); Nat Gen (2005); Nat Chem Biol (2005), Nat Neurosc (2007) GRK 1508 Scientific Environment: DFG Centre Grant SFB542 Molecular mechanisms of cytokine-driven inflammatory processes: EuCAR signal transduction and pathophysiologic consequences
Spokesman: Prof. Dr. Jürgen Floege GRK 1508 Scientific Environment: Interdisziplinäres Zentrum für Klinische Forschung (IZFF) EuCAR Molecular and technical therapy with endothelial progenitor cells
113-a Weber/Hristov/Balzer/Blindt: EPC Subpopulationen und Endothelfunktion 113-d Merx/Liehn: Rekrutierung endothelialer Progenitorzellen nach Myokardinfarkt 113-e Blindt/Gries/Kelm: Proendotheliale Stents mit Formgedächtnis 113-f Bernhagen/Schäfer/Koch/Weber: Rolle von MIF bei der Transplantation von eEPCs 113-g Zernecke/Klee/Möller/Gries: Wirkmechanismen von biofunktionaler Mini-Stents
Hristov et al., Blood (2004) Blindt et al., JACC (2006) Hristov et al., Circ. Res. (2007) Hristov & Weber, Curr. Opin. Lipidol. (2008) GRK 1508 Cardiovascular Research Institute Maastricht – CARIM EuCAR Scientific Director: Prof. Dr. Mat Daemen
Main Theme: Vascular Biology
Research School approved by Dutch Academy of Science 1992. Annual budget of 23 M €; 3 M € from NWO; 250 FTE researchers. GRK 1508 Technology: transgenic mice EuCAR
Cre-lox recombination: CXCR4 flox platelets: PF4-cre CXCR2 flox leukocytes: LysZ-cre JAM-Aflox SMCs: SM22-cre1Her SMC: SMMHC-creERT2 CCR1-/- arterial EC: Bmx-creERT2 CCR2-/- microvasc. EC: VECad-creERT2 CCR4-/- monocytes: c-fms-GFP CCR5-/- dendritic cells: CCL17-eGFP CCR7-/- CXCR6 e/e LacZ CX3CR1 e/e SM22-LacZ MIF-/- Tie2-LacZ CCL17 e/e Apoe-/-, LDLR-/- Generation of transgenic mice: SM22 α rtTA polyA
CX 3CL1sol/nc PF4-/- rtTA PF4alt doxycyclin flox SDF-1 t CMV CX3CL1 polyA
Inducible expression of CX3CL1 GRK 1508 Technology: 2-photon microscopy EuCAR Joint Professor for Biophysics
CCL17 e/e DAPI CX3CR1 e/e CD31 DAPI CX3CR1 e/e CD31 DAPI
2-photon microscopy (TPLSM)
Intravital microscopy (► EuCAR P4) GRK 1508 Stent technology & tissue engineering (P11 &14 ) EuCAR
cRGD control
BioSys Vascular Composite Graft based on co-scaffold of PLA and fibrin gel GRK 1508 Scientific Excellence EuCAR
• Strict criteria for eligibility for full professors (h>21) and associate professors (h>14) • Average h-index (defined by number of publications with >h citations) > 29 • Identical h-index average in Aachen & Maastricht for applicants and tenured assistants
Index original publications (Impact factor > 20 ) since 2002: 14x in total • Ostermann et al., Nature Immunology 2002 6x Nature Medicine • Ketteler et al., Lancet 2003 3x Nature Immunology • Huo et al., Nature Medicine 2003 4x Clinical Journals • Cao et al., Nature Medicine 2003 1x Nature • Autiero et al., Nature Medicine 2003 • Rassaf et al., Nature Medicine 2003 1x Nature Rev Immunol • Hacker et al., Nature Immunology 2003 1x Nat Drug Discovery • Heiss et al., JAMA 2003 • Kietselaer et al., N Engl J Med 2004 • Uhlig et al., Nature Medicine 2004 • Imai et al., Nature 2005 • Merx & Weber, Lancet 2006 • Weskamp et al., Nature Immunology 2006 • Bernhagen et al., Nature Medicine 2007 GRK 1508 Teaching Excellence & Collaborative Publications EuCAR
Teaching excellence follows scientific excellence: • >83 PhD or MD completed since 2003 each in Aachen and Maastricht (total >125 PhD) • 70% female gender (>30% tenure-track assistants)
Index Publications Aachen - Maastricht ( Impact factor >10):
• von Hundelshausen et al., Blood 2005;105:924 (Weber/Hackeng) • Lucerna et al., Blood 2007;109:122 (Biessen/Weber) • Bot et al., Circulation 2007;115:2516 (Biessen/Weber) • Krohn et al., Circulation 2007;116:1812 (Weber/Biessen) • Shagdarsuren et al., Circulation 2008;117:70 (Weber/Buurman) • Zernecke et al., Circ Res 2008;102:209 (Weber/Biessen) • Lutgens et al., Blood 2008; in press (Daemen/Weber) • Koenen et al., Nature Medicine 2008; in revision (Weber/Hackeng)
Examples to follow GRK 1508 Mast cell involvement in atherosclerosis EuCAR Cooperation between Biessen and Weber group
EuCAR P2 : Use of Wsh -/- mice deficient in mast cells and Ship -/- mice with constitutively active mast cell degranulation
Bot et al., Circulation (2007) GRK 1508 Complement inhibition blocks neointima formation EuCAR Cooperation between Weber and Buurman group
EuCAR P10 : Use of C5ar -/- mice and C5l2 -/- mice to delineate the role of complement receptors in neointimal hyperplasia
Shagdarsuren et al., Circulation (2008) GRK 1508 Additional Measures: EVGN EuCAR
Multiple EuCAR applicants are members or associates of EVGN or EVBI initiative: M. Daemen, C. Weber, E. Biessen, M. de Winther, E. Lutgens GRK 1508 Additional Measures: Soft Skills EuCAR
• General courses for PhD students in EuCAR 1. Statistics: part I (introduction) and part II (regression analysis) 2. Writing Scientific English (biomedical variant), parts I and II 3. Oral presentation in English (biomedical variant) 4. Animal handling in research 5. Introductory course on radiological research methods 6. Safe microbiological techniques
• Center for Doctoral Studies at RWTH Aachen 1. Embedding EuCAR & Medical Faculty 2. Scientific Methodology: data documentation, project management, communication skills, mile stone meetings, gender competence, etc. 3. Scientific Writing & Publishing: abstracts, original publications, reviews 4. Organising Seminars and International Conferences 5. Applications for Patents and External Funding 6. Plenary and interdisciplinary presentation training 7. 6 credit-points; similar ratio of obligatory modules & balance to thesis/papers
• NRW research school Biomedical Science & Engineering (pending) GRK 1508 Structural Features: Qualification Concept EuCAR
• Steering committee: - oversees, coordinates and updates teaching program based on evaluations - consults with thesis committees, reviews success and serves for mediation - decides on successful qualification phase for 12 months qualification scholars - coordinates invitations of guest scholars and master classes • Thesis committees: - constituted by one project leader/applicant each from Aachen and Maastricht and one independent project leader (interlinked with supervising group) - perform intake interview and generate individual PhD training & supervision plans, select obligatory modules based on previous experience, meet graduates bimonthly - control final credits and conduct PhD defense • Supervising group: - involving tenure-track assistants for day-to-day supervision and biweekly meetings
100 days in 3 years / biweekly supervising group / bimonthly thesis committee PhD CDS / Soft Skills Annual CDS / Soft Skills Annual CDS / Soft Skills Annual Intake Work- Work- Work- Method Modules Method Modules Method Modules Inter- Shop Shop Shop view 100 points2009 100 points 2010 100 points 2011 GRK 1508 EuCAR Training and Teaching Activities EuCAR at a glance
1. Aachen MD/PhD Program (www.ukaachen.de/content/folder/1784214 ) - Methods seminar (1st year) - Molecular Biology and Genetics (including MD students) - Molecular Pathogenesis in Organ Systems (2nd year) - Qualification profile Cell Biology and Molecular Genetics (also for PhDs) - Molecular Imaging 2. CARIM PhD Program Soft Skills - CDS - Introductory courses - Data Documentation & Statistics - Physiology and Biophysics of the heart and circulation - Scientific Writing & Publishing - Advanced microscopy and vital imaging - Oral & Plenary presentations - Clinical aspects of cardiovascular diseases - Animal Handling - Introduction into cardiovascular pharmacology - Biological-Radiology Safety - PhD-training courses - Organising Seminars & Meetings - Cardiac Function and Adaptation - Gender Competence - Vascular Biology - Patent Applications - Thrombosis and Haemostasis - External Funding Applications 3. EuCAR-specific Events (Co-organized by Graduates) - Progress Reports (once weekly) - Journal Club (once weekly) - Methods Seminar (once biweekly including an extensive set of monthly 1-day modules) - Clinical Excursions for Scientists - Annual EuCAR Meeting/Workshop (Abtei Rolduc, Kerkrade) 4. Lecture Series and Master Classes - Colloquium Molecular Medicine & Lecture Series in Vascular Biology (e.g. T. Springer, K. Ley) - Master Classes Aachen / Pfizer Lecture Maastricht (e.g. S. Dimmeler, A. Tedgui, A. Newby) GRK 1508 Overview of EuCAR Projects EuCAR
P1 Gene profiling of unstable atherosclerotic plaques Applicants: Zenke / Daemen , Assistants: Cleutgens/Hieronymus P2 Mast cells in arterial plaque destabilization Applicants: Weber / Biessen , Assistants: Zernecke/Shagdarsuren P3 Matrix Gla-protein (MGP) and arterial calcifications in fetuin-A-/- mice Applicants: Jahnen-Dechent / Floege / Vermeer , Assistants: Westenfeld/Schurgers P4 Two-photon microscopy for cell imaging in atherosclerotic arteries Applicants: Uhlig / Post , Assistants: Zernecke/van Zandvoort P5 Shedding of proatherogenic mediators from vascular cells Applicants: Ludwig / Hackeng , Assistants: von Hundelshausen/Koenen P6 The role of IKKs in atherosclerosis Applicants: Bernhagen / Weber / de Winther , Assistants: Zernecke/Lutgens P7 Molecular mechanisms of platelet microparticle formation Applicants: Weber / Heemskerk , Assistants: Kuijpers/Cauwenberghs/Koenen P8 Differential effects of angiogenic growth factors in monocyte subsets Applicants: Weber / Trautwein / Waltenberger , Assistants: Hristov/Tacke P9 The CD40/CD40L axis in arterial neointima formation Applicants: Weber / Daemen , Assistants: Hristov/Lutgens P10 Role of the complement cascade in arterial injury Applicants: Weber / Buurman , Assistants: Shagdarsuren P11 Arterialization of vein grafts in uremia Applicants: Floege / Jacobs , Assistants: Koeppel/Brandenburg/Tordoar P12 Cytoprotective effects of nitrite in ischemia / reperfusion injury Applicants: Kelm / Buurman , Assistant: Rassaf P13 MIF as a CXCR ligand in vasculaogenesis and therapeutic collateral growth/arteriogenesis Applicants: Bernhagen / Post , Assistants: Liehn/Steffens P14 Arterial tissue engineering: improving endothelial integrity and function Applicants: Schmitz-Rode / Kelm / Post , Assistants: Jockenhövel/Blindt/Hristov