Professorship for Experimental Hemostasis and Laboratory Medicine

Professor Sven Danckwardt, MD
Head of Experimental Hemostasis and Laboratory Medicine

The Module Experimental Hemostasis and Laboratory Medicine is mainly concerned with the underlying molecular principles of (de)regulated blood coagulation and the resulting implication for diagnostics and therapy.

In this context the module scientifically focuses on processes of posttranscriptional gene regulation and their role in the regulated (patho)physiology of blood coagulation (and beyond). We dissect gene regulatory mechanisms integrating environmental cues with the aim to understand how these mechanisms might explain previously enigmatic links between deregulated blood coagulation and tumor biology. The other main research focus of the lab is the intricate connection between blood coagulation, inflammation and immunity and how this contributes to various pathophysiologies.

Applying an integrative approach, all scientific topics include elements of basic research (biochemistry, molecular and cellular biology), modeling of diseases in animals and finally understanding the translational implications in patients. Complemented by novel diagnostic tools such as preclinical (molecular) optical imaging, we are aiming to illuminate such processes on a systems level non-invasively in living subjects. Our goal is to integrate this knowledge into novel therapeutic and diagnostic concepts.

We are constantly looking for talented scientists and students. If you are interested in joining our group or you need further information please do not hesitate to contact us.

Research Interests

• Posttranscriptional control of blood coagulation and beyond
• Role of blood coagulation in tumor biology and beyond (immunology)
• Significance of RNA regulation in development and disease (non coding RNAs, miRNAs, RNA binding proteins)

Important elements of our research are genetically engineered mouse models (GEMMs) as well as non-invasive preclinical  optical imaging.

In addition, we develop and apply next generation sequencing based diagnostic tools (sCLIP, TRENDseq, miTRAP) to decipher mechanisms of RNA regulation and to conduct large scale functional RNAi screening analyses. As an example, we recently released TREND-DB an unprecedented "complete" and freely accessible transcriptome database of the APA landscape (aka alternative polyadenylation) of more than 170 knockdown conditions (TREND-DB: explore interactively the dynamic landscape of transcriptome 3'end diversification)

Partners of Collaboration

• Hans Christian Probst, PhD (Institute of Immunology, University Medical Center Mainz)
• Prof. Stephan Macher-Göppinger, MD; Professor W. Roth, MD (Institute of Pathology/ NCT-tissue bank, DKFZ Heidelberg)
• Professor Tomasso Gori, MD (Department of Medicine 2, University Medical Center Mainz)
• Professor Pavel Ivanov (Department of Medicine/Rheumatology, Harvard Medical School, Boston USA)
• Professor Wolfram Ruf, MD (CTH & Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, USA)
• Professor Stefan Hüttelmaier (Institute of Molecular Medicine, Martin-Luther University Halle)
• Professor Bin Tian (Center for Genome Informatics and Department of Biochemistry and Molecular Biology, New Jersey Medical School, USA)
• Professor Michael Schäfer (Department  of Aneastesiology and Research Center for Translational Neurosciences, University Medical Center Mainz)
• Professor Frank Westermann, German Cancer Research Center (DKFZ), Germany
• Professor Ansgar Poetsch, Max-Planck-Institute for Heart and Lung Research, Germany /  School of Biomedical & Healthcare Sciences, Plymouth University

Research Funding

• German Research Foundation (DA 1189/2-1 und GRK 1591, University Halle)
• German Research Foundation (INST 371/33-1FUGG)
• Dr. Hella Bühler Award (Cancer Reserach)
• Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (DGKL)
• Alexander von Humboldt-Foundation

We are part of the DFG Priority Program 1935 - "Deciphering the mRNP code: RNA-bound Determinants of Posttranscriptional Gene Regulation",the TICARDIO EU Horizon 2020 Research consortium and the IMB International PhD Program.

Team - Module Experimental Hemostasis and Laboratory Medicine

MD Students

• Ludwig Eder, cand. med.
• Lisa Pruschinski, cand. med., DCF Fellow
• Lina Schott, cand. med., DGKL MD Fellowship (former DCF Fellow)
• Nurten Defne Cetiner, cand. med., DCF Fellow
• Jonas Niedenthal, cand. med., DCF Fellow
• Constantia Müller, cand. med., DCF Fellow
• Ann-Celine Mathmann, cand. med.
• Maria Elsbernd, cand. med. dent.
• Sophie Hartleb, cand. med.

Master Students

• Svetlana Pavicevic

Alumni

• Dr. Michal Levin, Postdoctoral Scientist, IMB Mainz
• Dr. rer. nat. Shazad Khokhar, Postdoctoral Scientist, Harvard Medical School, USA
• Dr. rer. nat. Anton Ogorodnikov, Postdoctoral Scientist, McManus Laboratory, UCSF 
• Dr. rer. nat. Yulia Kargapolova, Postdoctoral Scientist, Papantonis lab, Cologne
• Dr. rer. nat. Sergey Tokalov, Senior Postdoc, Animal Imaging, Clinical Chemistry and Laboratory Medicine, University Mannheim
• Dr. sc. hum. Kashif Muhammad, Postdoctoral Scientist, Clinical Chemistry and Laboratory Medicine, University Mannheim
• Dr. rer. nat. Kathleen Mühlbach
• Ranya Al Shekaki, MSc

Reviews

• Ogorodnikov A, Danckwardt S. TRENDseq—A highly multiplexed high throughput RNA 3′ end sequencing for mapping alternative polyadenylation Methods in Enzymology, Book Chapter in press, available online 26 May 2021
• Nourse J, Danckwardt S. A novel rationale for targeting FXI: Insigh May ts from the hemostatic miRNA targetome for emerging anticoagulant strategies. Pharmacol Ther 2020 doi:10.1016/j.pharmthera.2020.107676:107676.
• Nourse J, Spada S, Danckwardt S. Emerging Roles of RNA 3'-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders. Biomolecules 2020;10(6).
•  Ogorodnikov, A., Y. Kargapolova and S. Danckwardt (2016). Processing and transcriptome expansion at the mRNA 3' end in health and disease: finding the right end. Pflugers Arch 468(6): 993-1012.
• Krenzlin H, Lorenz V, Danckwardt S, Kempski O, Alessandri B. The Importance of Thrombin in Cerebral Injury and Disease. International journal of molecular sciences 17. 2016.
• Danckwardt S, Hentze MW, Kulozik AE. Pathologies at the nexus of blood coagulation and inflammation: Thrombin in Hemostasis, Cancer and beyond. J Mol Med. 91(11):1257-71. PMID:23955016, 2013.
• Matthias W. Hentze and Andreas E. Kulozik. Krebs, Blutgerinnung und Stress – eine ungewöhnliche Ménage-à-trois.
• Danckwardt S, Hentze MW, Kulozik AE.3' end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J. 6;27(3):482-98, 2008.
• Danckwardt S, Hartmann K, Gehring NH, Hentze MW, Kulozik AE. 3' end processing of the prothrombin mRNA in thrombophilia. Acta Haematol. 115(3-4):192-7, 2006.

Selected original articles

• Marini F, Scherzinger D, Danckwardt S. TREND-DB - A Transcriptome-wide Atlas of the Dynamic Landscape of Alternative Polyadenylation. Nucleic Acids Res 2020 accepted

• Ma, J, Klemm J, Ramírez MG, Frappart, L… Danckwardt S…. Marquardt JU, Hartmann M. CD44 (Cluster of differentiation 44) promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin. Int J Cancer (accepted)

• Schaupp L, Muth S, Rogell L, Kofoed-Branzk M, Melchior F, Lienenklaus S, Ganal-Vonarburg SC, Klein M, Guendel F, Hain T, Schutze K, Grundmann U, Schmitt V, Dorsch M, Spanier J, Larsen PK, Schwanz T, Jäckel S, Reinhardt C, Bopp T, Danckwardt S, Mahnke K, Heinz GA, Mashreghi MF, Durek P, Kalinke U, Kretz O, Huber TB, Weiss S, Wilhelm C, Macpherson AJ, Schild H, Diefenbach A, Probst HC. Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells. Cell 2020;181(5):1080-1096 e1019.

• Häuser F, Gokce S, Werner G, Danckwardt S, Sollfrank S, Neukirch C, Beyer V, Hennermann JB, Lackner KJ, Mengel E, Rossmann H. A non-invasive diagnostic assay for rapid detection and characterization of aberrant mRNA-splicing by nonsense mediated decay inhibition. Mol Genet Metab 2020;130(1):27-35.

• Panova-Noeva M, Wagner B, Nagler M, Arnold N, Prochaska JH, Eckerle S, Spronk HM, Merzenich H, Wingerter A, Schneider A, Danckwardt S, Ten Cate H, Faber J, Wild PS. Relation between platelet coagulant and vascular function, sex-specific analysis in adult survivors of childhood cancer compared to a population-based sample. Sci Rep 2019;9(1):20090.

• Hain T, Melchior F, Kamenjarin N, Muth S, Weslati H, Clausen BE, Mahnke K, Silva-Vilches C, Schutze K, Sohl J, Radsak MP, Bundgen G, Bopp T, Danckwardt S, Schild H, Probst HC. Dermal CD207-Negative Migratory Dendritic Cells Are Fully Competent to Prime Protective, Skin Homing Cytotoxic T-Lymphocyte Responses. J Invest Dermatol 2019;139(2):422-429.

• Ogorodnikov A, Levin M, Tattikota S, Tokalov S, Hoque M, Scherzinger D, Marini F, Poetsch A, Binder H, Macher-Göppinger S, Probst HC, Tian B, Schaefer M, Lackner KJ, Westermann F, Danckwardt S. Transcriptome 3'end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma. Nat Commun 2018;9(1):5331.

• Nourse J, Danckwardt S. A novel rationale for targeting FXI: Insights from the hemostastic miRNA targetome for emerging anticoagulant strategies. BioRxiv 2018. https://doi.org/10.1101/501676

• Nourse J, Braun J, Lackner K, Huttelmaier S, Danckwardt S. Large-scale identification of functional microRNA targeting reveals cooperative regulation of the hemostatic system. J Thromb Haemost 2018;16(11):2233-2245.

• Kargapolova Y, Levin M, Lackner K, Danckwardt S (2017) sCLIP-an integrated platform to study RNA-protein interactomes in biomedical research: identification of CSTF2tau in alternative processing of small nuclear RNAs. Nucleic Acids Res 2017;45(10):6074-6086.

• Steven S, Jurk K, Kopp M, Kröller-Schön S, Mikhed Y, Schwierczek K, Roohani S, Kashani F, Oelze M, Klein T, Tokalov S, Danckwardt S, Strand S, Wenzel P, Münzel T, Daiber A. (2016). Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice. Br J Pharmacol. 2017;174(12):1620-1632.

• Danckwardt S, Gantzert AS, Macher-Goeppinger S, Probst HC, Gentzel M, Wilm M et al. p38 MAPK Controls Prothrombin Expression by Regulated RNA 3' End Processing. Mol Cell. 41(3):298-310, 2011.

• Danckwardt S, Kaufmann I, Gentzel M, Foerstner KU, Gantzert AS, Gehring NH, Neu-Yilik G, Bork P, Keller W, Wilm M, Hentze MW, Kulozik AE. Splicing factors stimulate polyadenylation via USEs at non-canonical 3' end formation signals. The EMBO journal. 26:2658-2669, 2007.

• Danckwardt S, Hartmann K, Katz B, Hentze MW, Levy Y, Eichele R, Deutsch V, Kulozik AE, Ben-Tal O.The prothrombin 20209 C-->T mutation in Jewish-Moroccan Caucasians: molecular analysis of gain-of-function of 3' end processing. J Thromb Haemost. 4(5):1078-85, 2006.

• Danckwardt S, Gehring NH, Neu-Yilik G, Hundsdoerfer P, Pforsich M, Frede U, Hentze MW, Kulozik AE.The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations. Blood. 104(2):428-35, 2004.

• Danckwardt S, Neu-Yilik G, Thermann R, Frede U, Hentze MW, Kulozik AE. Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay. Blood. 99:1811-1816, 2002.

TREND-DB: explore interactively the dynamic landscape of transcriptome 3'end diversification (TREND)