SFB 656:  Molecular Cardiovascular Imaging (MoBil) - From Mouse to Man

• Subject Area: Medicine ; Biology ; Chemistry ; Computer Science, Systems and Electrical Engineering ; Mathematics
• Term: from 2005 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 12467772

• Final Report Year: 2017

Final Report Abstract

The Collaborative Research Centre CRC 656 ‘Molecular cardiovascular imaging’ was initiated at the University of Münster (Westfälische Wilhelms-Universität Münster, WWU) with the aim to develop and establish novel molecular imaging approaches for studying functional and molecular aspects of cardiovascular diseases and their clinical sequelae. A particular emphasis was put on developing molecular imaging towards bridging preclinical models of human pathologies and clinical disease, in scenarios such as atherosclerosis, myocardial infarction or arrhythmia and cardiomyopathies. Already from the start the scientific concept was based on a strong inter-faculty co-operation between the faculties of medicine, chemistry and pharmacy, physics and mathematics and computer sciences and the Max Planck Institute for Molecular Biomedicine in Münster in the areas of preclinical models and translational research, organic chemistry and radiochemistry, detector physics and image reconstruction and processing. With its research topic and inter-faculty setup, CRC 656 was the first dedicated imaging CRC funded by the DFG. Scientists of CRC 656 successfully worked on various projects and published distinguished scientific results and patents in the various areas of CRC 656 research. CRC 656 has fostered basic research by developing and applying novel molecular imaging technologies as well as first examples of the translational potential of these approaches to interrogate cardiovascular diseases. These scientific results have been discussed in three international Molecular Imaging Schools organised by CRC 656, where PIs of our CRC interacted with internationally recognized scientists from all relevant research areas. At the same time, CRC 656 has driven a broad interdisciplinary and inter-faculty network at WWU that has successfully overcome pre-existing faculty borders. This was realised through interdisciplinary multi-PI projects as well as interdisciplinary supervision of doctoral students and their projects. The cross-faculty approach of CRC 656 has been the basis for the establishment of new structures at WWU, e.g. the European Institute for Molecular Imaging – EIMI as a central interdisciplinary research unit, which further promoted the inter-faculty endeavour of CRC 656 as well as laid the basis for new and even broader research networks. Amongst others, the successful application for the DFG Cluster of Excellence ‘Cells in Motion – CiM’ picked up the idea of CRC 656 to use imaging to bridge scales and fields and expanded it to high resolution approaches and a broader biomedical field. In addition, CRC 656 has developed a strong public outreach programme, which targeted scholars, school teachers and the public through a broad range of talks, workshops and interactive exhibitions. These activities were funded in one of the early Ö-projects in a CRC in Germany. In summary, CRC 656 has largely accomplished its scientific mission, has promoted new inter-faculty structures and thereby significantly contributed to the international scientific visibility and attractiveness of WWU.

Publications

• 5-Pyrrolidinylsulfonyl isatin derivatives. WO 2006/074799; 20/07/2006
  Kopka K, Levkau B, Schäfers M
  
• Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 2006;114: 1799-1806
  Kirchhof P, Fabritz L, Zwiener M, Witt H, Schäfers M, Zellerhoff S, Paul M, Athai T, Hiller K-H, Baba HA, Breithardt G, Ruiz P, Wichter T, Levkau B
  
• High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation 2006;114: 1403-1409
  Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I, Mersmann J, Larmann J, Hermann S, Stypmann J, Schober O, Hildebrand R, Schulz R, Heusch G, Haude M, von Wnuck Lipinski K, Herzog C, Schmitz M, Erbel R, Chun J, Levkau B
  
• A fluorescent photoprobe for the imaging of endothelin receptors. 2007/028599; 15/03/2007
  Bremer C, Höltke C, Kopka K, Schäfers M
  
• Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET. J Med Chem 2007;50: 5752-5764
  Wagner S, Breyholz H-J, Law MP, Faust A, Höltke C, Schroer S, Haufe G, Levkau B, Schober O, Schäfers M, Kopka K
  
• Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography. Blood 2008;111: 2909-2918
  Stelljes M, Hermann S, Albring J, Kohler G, Loffler M, Franzius C, Poremba C, Schlosser C, Volkmann S, Opitz C, Bremer C, Kucharzik T, Silling G, Schober O, Berdel WE, Schäfers M, Kienast J
  
• Fluorescence reflectance imaging of macrophage-rich atherosclerotic plaques using an alphavbeta3 integrin-targeted fluorochrome. J Nucl Med 2008;49: 1845-1851
  Waldeck J, Hager F, Höltke C, Lanckohr C, von Wallbrunn A, Torsello G, Heindel W, Theilmeier G, Schäfers M, Bremer C
  
• Respiratory motion correction in 3-D PET data with advanced optical flow algorithms. IEEE Trans.Med.Imaging 2008;27: 1164-1175
  Dawood M, Büther F, Jiang X, Schäfers KP
  
• Survivin determines cardiac function by controlling total cardiomyocyte number. Circulation 2008;117: 1583-1593
  Levkau B, Schäfers M, Wohlschlaeger J, von Wnuck Lipinski K, Keul P, Hermann S, Kawaguchi N, Kirchhof P, Fabritz L, Stypmann J, Stegger L, Flogel U, Schrader J, Fischer JW, Hsieh P, Ou YL, Mehrhof F, Tiemann K, Ghanem A, Matus M, Neumann J, Heusch G, Schmid KW, Conway EM, Baba HA
  
• New N- Substituted 5-Pyrrolidinylsulfonyl Isatins as Potential Tools for Imaging of Caspases in Apoptosis by Positron Emission Tomography. J Med Chem 2009;52: 3484-3495
  Podichetty AK, Wagner S, Kopka K, Schröer S Faust A Schäfers M, Schober O, Haufe G
  
• Noninvasive imaging of acute renal allograft rejection in rats using small animal F-FDG-PET. PLoS One 2009;4: e5296
  Reuter S, Schnöckel U, Schroter R, Schober O, Pavenstädt H, Schäfers M, Gabriels G, Schlatter E
  
• Quantification of left ventricular volumes and ejection fraction in mice using PET, compared with MRI. J Nucl Med 2009;50: 132-138
  Stegger L, Heijman E, Schäfers KP, Nicolay K, Schäfers MA, Strijkers GJ
  
• Isochronous assessment of cardiac metabolism and function in mice using hybrid PET/MRI. J Nucl Med 2010;51: 1277-1284
  Buscher K, Judenhofer MS, Kuhlmann MT, Hermann S, Wehrl HF, Schäfers KP, Schäfers M, Pichler BJ, Stegger L
  
• Motion correction in Positron Emission Tomography considering Partial Volume Effects in optical flow estimation. IEEE ISBI 2010: 1233-1236
  Tenbrinck D, Dawood M, Gigengack F, Fieseler M, Jiang X, Schäfers K
  
• (2011) 2010 IEEE Visualization Contest Winner: interactive planning for brain tumor resections. In: IEEE computer graphics and applications 31 (5) 6–13
  Diepenbrock S, Praßni J S, Lindemann F, Bothe H W, Ropinski T
  (See online at https://doi.org/10.1109/MCG.2011.70)
• Cardiac Sympathetic Dysfunction in Genotyped Patients with Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Recurrent Ventricular Tachyarrhythmias. J Nucl Med 2011;52: 1559-65
  Paul M, Wichter T, Kies P, Gerss J, Wollmann C, Rahbar K, Eckardt L, Breithardt G, Schober O, Schulze- Bahr E, Schäfers M
  
• Hydroxyfasudil-mediated inhibition of ROCK1 and ROCK2 improves kidney function in rat renal acute ischemia-reperfusion injury. PLoS One 2011;6: e26419
  Kentrup D, Reuter S, Schnöckel U, Grabner A, Edemir B, Pavenstädt H, Schober O, Schäfers M, Schlatter E, Bussemaker E
  
• Mass-preserving motion correction of PET: Displacement field vs spline transformation. IEEE NSS/MIC 2011: 3088-3090
  Gigengack F, Ruthotto L, Burger M, Wolters CH, Jiang X, Schäfers KP
  
• Novel diagnostic agents for the non-invasive in vivo optical imaging of aminopeptidase N. WO 2011/026824; 10/03/2011
  Bremer C, Höltke C
  
• Preload-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. J Am Coll Cardiol 2011;57: 740-750
  Fabritz L, Hoogendijk MG, Scicluna BP, van Amersfoorth SCM, Fortmueller L, Wolf S, Laakmann S, Kreienkamp N, Piccini I, Breithardt G, Ruiz Noppinger P, Witt H, Ebnet K, Wichter T, Levkau B, Franke WW, Pieperhoff S, de Bakker JMT, Coronel R, Kirchhof P
  
• Compounds with matrix-metalloproteinase inhibitory activity. EP 2520573; 07/11/2012
  Behrends M, Breyholz HJ, Hermann S, Haufe G, Hugenberg V, Kolb H, Kopka K, Wagner S, Schäfers M
  
• Early detection of lung inflammation: Exploiting T1-effects of iron oxide particles using UTE MRI. Magn Reson Med 2012;68: 1924-1931
  Strobel K, Hörr V, Schmid F, Wachsmuth L, Löffler B, Faber C
  (See online at https://doi.org/10.1002/mrm.24180)
• A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO J 2013;32: 629-644
  Hägerling R, Pollmann C, Andreas M, Schmidt C, Nurmi H, Adams RH, Alitalo K, Andresen V, Schulte-Merker S, Kiefer F
  (See online at https://doi.org/10.1038/emboj.2012.340)
• Compounds with matrixmetalloproteinase inhibitory activity. WO 2013/010573; 24/01/2013
  Haufe G, Hermann S, Hugenberg V, Kolb H, Kopka K, Wagner S, Schäfers M
  
• Method and system for image segmentation. EP 2645329; 02/10/2013
  Tenbrinck D, Stypmann J, Jiang X
  
• New ligands for targeting of S1P receptors for in vivo imaging and treatment of diseases. WO 2013/026765; 28/02/2013
  Haufe G, Schilson S, Keul P, Levkau B, Schäfers M
  
• Synthesis, 18F-radiolabeling, and in vivo biodistribution studies of N-fluorohydroxybutyl isatin sulfonamides using positron emission tomography. J Med Chem 2013;56: 4509-4520
  Limpachayaporn P, Wagner S, Kopka K, Hermann S, Schäfers M, Haufe G
  (See online at https://doi.org/10.1021/jm400257a)
• Towards Quantitative Image Reconstruction Using Monte-Carlo Simulations in Multi-Wire Proportional Chamber- Based Small Animal PET. IEEE Trans Nucl Sci 2013;60: 3343-3354
  Gottschlag H, Kösters T, Vernekohl D, Reygers K, Schäfers KP, Wübbeling F, Wessels JP
  (See online at https://doi.org/10.1109/TNS.2013.2274703)
• Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity. Nat Commun 2014;5: 4593
  Vogl T, Eisenblätter M, Voller T, Zenker S, Hermann S, van Lent P, Faust A, Geyer C, Petersen B, Roebrock K, Schäfers M, Bremer C, Roth J
  (See online at https://doi.org/10.1038/ncomms5593)
• Fluorescent Non-peptidic RGD Mimetics with High Selectivity for alphaVbeta3 vs alphaIIbbeta3 Integrin Receptor: Novel Probes for in Vivo Optical Imaging. J Med Chem 2014;57: 9971-9982
  Alsibai W, Hahnenkamp A, Eisenblatter M, Riemann B, Schäfers M, Bremer C, Haufe G, Höltke C
  (See online at https://doi.org/10.1021/jm501197c)
• Highly Shifted Proton MR Imaging: Cell Tracking by Using Direct Detection of Paramagnetic Compounds. Radiology 2014;272: 785-795
  Schmidt R, Nippe N, Strobel K, Masthoff M, Reifschneider O, Castelli DD, Höltke C, Aime S, Karst U, Sunderkötter C, Bremer C, Faber C
  (See online at https://doi.org/10.1148/radiol.14132056)
• Mechanisms of infective endocarditis: pathogen-host interaction and risk states. Nat Rev Cardiol 2014;11: 35-50
  Werdan K, Dietz S, Löffler B, Niemann S, Bushnaq H, Silber RE, Peters G, Müller-Werdan U
  (See online at https://doi.org/10.1038/nrcardio.2013.174)
• MRI Visualization of Staphyloccocus aureus-Induced Infective Endocarditis in Mice. PLoS One 2014;9: e107179
  Ring J, Hörr V, Tuchscherr L, Kuhlmann MT, Löffler B, Faber C
  (See online at https://doi.org/10.1371/journal.pone.0107179)
• Serial F-18-FDG PET/CT distinguishes inflamed from stable plaque phenotypes in shear-stress induced murine atherosclerosis. Atherosclerosis 2014;234: 276-282
  Wenning C, Kloth C, Kuhlmann MT, Jacobs AH, Schober O, Hermann S, Schäfers MA
  (See online at https://doi.org/10.1016/j.atherosclerosis.2014.03.008)
• Total variation regularization in measurement and image space for PET reconstruction. Inverse Probl 2014;30: 105003
  Burger M, Müller J, Papoutsellis E, Schönlieb CB
  (See online at https://doi.org/10.1088/0266-5611/30/10/105003)
• Focal MMP-2 and MMP-9 Activity at the Blood-Brain Barrier Promotes Chemokine- Induced Leukocyte Migration. Cell Rep 2015;10: 1040-1054
  Song J, Wu C, Korpos E, Zhang X, Agrawal SM, Wang Y, Faber C, Schäfers M, Korner H, Opdenakker G, Hallmann R, Sorokin L
  (See online at https://doi.org/10.1016/j.celrep.2015.01.037)
• Quinoline-3-carboxamide compounds and their use in diagnosis. PCT/IB2015/058348
  Hermann S, Vogl T, Faust A, Roth J, Schäfers M
  
• Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin. Nat Commun 2015;6: 6416
  Nussbaum C, Bannenberg S, Keul P, Graler MH, Goncalves-de-Albuquerque CF, Korhonen H, von Wnuck Lipinski K, Heusch G, de Castro Faria Neto HC, Rohwedder I, Gothert JR, Prasad VP, Haufe G, Lange- Sperandio B, Offermanns S, Sperandio M, Levkau B
  (See online at https://doi.org/10.1038/ncomms7416)
• Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography. J Med Chem 2015;58: 3471-3484
  Shaikh RS, Schilson SS, Wagner S, Hermann S, Keul P, Levkau B, Schäfers M, Haufe G
  (See online at https://doi.org/10.1021/jm502021d)
• Velocity mapping of the aortic flow at 94 T in healthy mice and mice with induced heart failure using time-resolved three-dimensional phase-contrast MRI (4D PC MRI). Magma 2015;28: 315-327
  Bovenkamp PR, Brix T, Lindemann F, Holtmeier R, Abdurrachim D, Kuhlmann MT, Strijkers GJ, Stypmann J, Hinrichs KH, Hörr V
  (See online at https://doi.org/10.1007/s10334-014-0466-z)
• A Comparison of Different Algorithms for the Assessment of Cardiovascular Risk in Patients at Waiting List for Kidney Transplantation. PLoS One 2016;11: e0161927
  Reuter S, Reiermann S, Malyar V, Schütte-Nütgen K, Schmidt R, Pavenstädt H, Reinecke H, Suwelack B
  (See online at https://doi.org/10.1371/journal.pone.0161927)
• A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level. Embo J 2016;35: 102-113
  Erapaneedi R, Belousov VV, Schäfers M, Kiefer F
  (See online at https://doi.org/10.15252/embj.201592775)
• Imaging Reveals the Connection Between Spontaneous Coronary Plaque Ruptures, Atherothrombosis, and Myocardial Infarctions in HypoE/SRBI-/- Mice. J Nucl Med 2016;57: 1420-1427
  Hermann S, Kuhlmann MT, Starsichova A, Eligehausen S, Schäfers K, Stypmann J, Tiemann K, Levkau B, Schäfers M
  (See online at https://doi.org/10.2967/jnumed.115.171132)
• Impact of Data-driven Respiratory Gating in Clinical PET. Radiology 2016: 152067
  Büther F, Vehren T, Schäfers KP, Schäfers M
  (See online at https://doi.org/10.1148/radiol.2016152067)
• Sphingosine-1-Phosphate Receptor 1 Regulates Cardiac Function by Modulating Ca2+ Sensitivity and Na+/H+ Exchange and Mediates Protection by Ischemic Preconditioning. J Am Heart Assoc 2016;5: e003393
  Keul P, van Borren MMGJ, Ghanem A, Muller FU, Baartscheer A, Verkerk AO, Stumpel F, Schulte JS, Hamdani N, Linke WA, van Loenen P, Matus M, Schmitz W, Stypmann J, Tiemann K, Ravesloot J-H, Alewijnse AE, Hermann S, Spijkers LJA, Hiller K-H, Herr D, Heusch G, Schäfers M, Peters SLM, Chun J, Levkau B
  (See online at https://doi.org/10.1161/JAHA.116.003393)
• (2017). A mutation in the G-protein gene GNB2 causes familial sinus node and atrioventricular conduction dysfunction. Circulation research, 120(10), e33-e44
  Stallmeyer B, Kuss J, Kotthoff S, Zumhagen S, Vowinkel KS, Rinne S, Matschke LA, Friedrich C, Schulze- Bahr E, Rust S, Seebohm G, Decher N, Schulze-Bahr E
  (See online at https://doi.org/10.1161/CIRCRESAHA.116.310112)
• A Novel Mouse Model of Staphylococcus aureus Vascular Graft Infection: Noninvasive Imaging of Biofilm Development in Vivo. Am J Pathol 2017;187: 268-279
  Van de Vyver H, Bovenkamp PR, Hörr V, Schwegmann K, Tuchscherr L, Niemann S, Kursawe L, Grosse C, Moter A, Hansen U, Neugebauer U, Kuhlmann MT, Peters G, Hermann S, Löffler B
  (See online at https://doi.org/10.1016/j.ajpath.2016.10.005)
• Data-Driven Methods for the Determination of Anterior-Posterior Motion in PET. IEEE Trans Med Imaging 2017;36: 422-432
  Hess M, Büther F, Schäfers KP
  (See online at https://doi.org/10.1109/TMI.2016.2611022)