Research Area I: Molecular Signature Analysis for Individualised Therapy
| Research Area Leaders | |
|---|---|
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Kerckhoff-Klinik Benekestrasse 2-8 61231 Bad Nauheim |
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MPI for Heart and Lung Research Parkstrasse 1 31231 Bad Nauheim |
| Faculty involved | ||||
|---|---|---|---|---|
| S. Achenbach | T. Braun | S. Dimmeler | S. Fichtlscherer | I. Fleming |
| H.A. Ghofrani | F. Grimminger | A. Günther | C.W. Hamm | M. Krüger |
| W. Kummer | E. Mayer | M. Potente | K.T. Preissner | R.T. Schermuly |
| D. Sedding | W. Seeger | R. Voswinckel | M.R. Wilkins | A.M. Zeiher |
Summary
Achievements of ECCPS members in this field include the characterisation of circulating biomarkers of coronary artery disease and cardiomyopathy such as; high sensitivity troponin, BNP and its metabolites, sCD40L and PlGF. The search for biomarkers of tissue ischemia that precede biomarkers of necrosis, identified soluble Flt-1 as being produced by the hypoxia induced activation of Jmjd6-controlled alternative splicing. Flt-1 is therefore a potential prognostic marker of acute coronary syndrome as well as pulmonary hypertension. Furthermore, we have identified vascular endothelial-, smooth muscle cell-, and cardiomyocyte-specific microRNA (miR). The stability of miR in the blood and their reproducible detection has recently been demonstrated by this area and the validation of miR as putative biomarkers of vascular disease, ischemia and heart failure is a major goal for the next funding period. We will also focus on identifying the mechanisms of miR release and their stabilisation in plasma by specific binding proteins. Several large biobanks comprising various cardiovascular and pulmonary vascular diseases have been established as a core for novel biomarker evaluation. To identify very early markers of tissue hypoxia and ischemia, the transcoronary ablation of septum hypertrophy procedure will be used as a human model system of controlled myocardial infarction. Likewise, the surgical desobliteration of chronic thromboembolic occluded pulmonary arteries by endarterectomy will be used to identify mechanisms and biomarkers of right heart load, failure and recovery (reverse remodelling). Finally, this area aims at the in vivo validation of molecular signature analysis by molecular imaging in the designated ECCPS imaging centre.
Most relevant publications of the Research Area I
1. De Rosa S, Fichtlscherer S, Lehmann R, Assmus B, Dimmeler S, Zeiher AM. Transcoronary concentration gradients of circulating miRNAs. Circulation. In press 2011
2. Schnütgen F, Ehrmann F, Poser I, Hubner NC, Hansen J, Floss T, deVries I, Wurst W, Hyman A, Mann M, von Melchner H. Resources for proteomics in mouse embryonic stem cells. Nat Methods 8:103-4, 2011
3. Boeckel JN, Guarani V, Koyanagi M, Roexe T, Lengeling A, Schermuly RT, Gellert P, Braun T, Zeiher A, Dimmeler S. Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. Proc Natl Acad Sci USA 108:3276-81, 2011
4. Urbich C, De Souza AI, Rossig L, Yin X, Xing Q, Prokopi M, Drozdov I, Steiner M, Breuss J, Xu Q, Dimmeler S, Mayr M. Proteomic characterization of human early pro-angiogenic cells. J Mol Cell Cardiol 50:333-6, 2011
5. Achenbach S, Marwan M, Ropers D, Schepis T, Pflederer T, Anders K, Kuettner A, Daniel WG, Uder M, Lell MM. Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J 31:340-6, 2010
6. Dimmeler S, Zeiher AM. Circulating microRNAs: novel biomarkers for cardiovascular diseases? Eur Heart J 31:2705-7
7. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S., Circulating microRNAs in patients with coronary artery disease. Circ Res 107:677-84, 2010
8. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 182:1171-7, 2010
9. Grimminger F, Schermuly RT, Ghofrani HA. Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov 912:956-70,2010
10. Hecker M, Zaslona Z, Kwapiszewska G, Niess G, Zakrzewicz A, Hergenreider E, Wilhelm J, Marsh LM, Sedding D, Klepetko W, Lohmeyer J, Dimmeler S, Seeger W, Weissmann N, Schermuly RT, Kneidinger N, Eickelberg O, Morty RE. Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med 182:805-18, 2010
11. Kreymborg K, Uchida S, Gellert P, Schneider A, Boettger T, Voswinckel R, Wietelmann A, Szibor M, Weissmann N, Ghofrani AH, Schermuly R, Schranz D, Seeger W, Braun T Identification of right heart-enriched genes in a murine model of chronic outflow tract obstruction. J Mol Cell Cardiol 49: 598-605, 2010
12. Looso M, Borchardt T, Krüger M, Braun T. Advanced identification of proteins in uncharacterized proteomes by pulsed in vivo SILAC. Mol Cell Proteom 9, 1157-66, 2010
13. ten Berg JM, van ´t Hof AW, Dill T, Heestermans T, van Werkum JW, Mosterd A, van Houwelingen G, Koopmans PC, Stella PR, Boersma E, Hamm C; On-TIME 2 Study Group. Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome.J Am Coll Cardiol 55:2446-55, 2010
14. Boettger T, Beetz N, Kostin S, Schneider J, Krüger M, Hein L, Braun T. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest 119:2634-47, 2009
15. Hausleiter J, Meyer T, Hermann F, Hadamitzky M, Krebs M, Gerber TC, McCollough C, Martinoff S, Kastrati A, Schömig A, Achenbach S. Estimated radiation dose associated with cardiac CT angiography. JAMA 301:500-7, 2009
16. Spyridopoulos I, Hoffmann J, Aicher A, Brümmendorf TH, Doerr HW, Zeiher AM, Dimmeler S. Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation 120:1364-72, 2009
17. Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX. A functional single nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119: 2313-22, 2009
18. Eikelboom JW, Hankey GJ, Thom J, Bhatt DL, Steg PG, Montalescot G, Johnston SC, Steinhubl SR, Mak KH, Easton JD, Hamm C, Hu T, Fox KA, Topol EJ; Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Investigators Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation 118:1705-12, 2008
19. Krüger M, Moser M, Ussar S, Thievessen I, Luber CA, Forner F, Schmidt S, Zanivan S, Fässler R, Mann M. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function Cell 134:353-64, 2008
20. Kwapiszewska G, Wygrecka M, Marsh LM, Schmitt S, Trösser R, Wilhelm J, Helmus K, Eul B, Zakrzewicz A, Ghofrani HA, Schermuly RT, Bohle RM, Grimminger F, Seeger W, Eickelberg O, Fink L, Weissmann N. Fhl-1, a new key protein in pulmonary hypertension. Circulation 118:1183-94, 2008
21. Serruys PW, García-García HM, Buszman P, Erne P, Verheye S, Aschermann M, Duckers H, Bleie O, Dudek D, Bøtker HE, von Birgelen C, D´Amico D, Hutchinson T, Zambanini A, Mastik F, van Es GA, van der Steen AF, Vince DG, Ganz P, Hamm CW, Wijns W, Zalewski A; Integrated Biomarker and Imaging Study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118:1172-82, 2008
22. Schächinger V, Aicher A, Döbert N, Röver R, Diener J, Fichtlscherer S, Assmus B, Seeger FH, Menzel C, Brenner W, Dimmeler S, Zeiher AM. Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium. Circulation 118:1425-32, 2008
23. Weber M, Bazzino O, Navarro Estrada JL, Fuselli JJ, Botto F, Perez de Arenaza D, Möllmann H, Nef HN, Elsässer A, Hamm CW, N-terminal B-type natriuretic peptide assessment provides incremental prognostic information in patients with acute coronary syndromes and normal troponin T values upon admission. J Am Coll Cardiol 51:1188-95, 2008
24. Weber M, Hamm C, Novel biomarkers--the long march from bench to bedside. Eur Heart J 29: 1079-81, 2008
25. Erbs S, Linke A, Schachinger V, Assmus B, Thiele H, Diederich KW, Hoffmann C, Dimmeler S, Tonn T, Hambrecht R, Zeiher AM, Schuler G. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 116:366-74, 2007
26. Pingoud A, Silva GH. Precision genome surgery. Nat Biotechnol 25:743-44, 2007
27. Sedding D, Daniel JM, Muhl L, Hersemeyer K, Brunsch H, Kemkes-Matthes B, Braun- Dullaeus RC, Tillmanns H, Weimer T, Preissner KT, Kanse SM. The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation. J Exp Med 203:2801-7, 2006
28. PATENT: Zeiher, A, Dimmeler S, Heeschen C. In vitro method for the diagnosis of cardiovascular functionality of bone marrow precursor cells (BMP) and/or circulation precursor cells derived from blood (BDP) DE 10253526 granted 2.8.2007; US Patent 7919315B2 granted 5.4.2011
29. PATENT: Zeiher, A, Dimmeler S, Heeschen C PIGF and Flt-1 as prognostic parameters for cardiovascular disease EP 1807702 granted 5.8.2009
30. PATENT: Dimmeler S, Zeiher, AM, Nef H, Ghofrani, A, Hamm C, Grimminger, F, Möllmann H, Schermuly R. sFLT and PlGF as novel biomarkers in pulmonary hypertension Prio DE 10 2010 013 555.0 am 31.03.2010