Alexander von Humboldt-Professorship

Professor Wolfram Ruf, MD
Professorship for Cell Signaling Pathways of the Hemostatic System

The hemostatic system is comprised of the coagulation and fibrinolytic protease cascades, platelets, and cellular receptors on immune and vascular cells. The hemostatic response to infection and tissue injury supports inflammatory and immune reactions, but the coagulation pathways are increasingly recognized as major players and molecular targets for interventional therapy in cancer progression, atherosclerosis, chronic inflammatory disorders, and the metabolic syndrome associated with obesity. We are interested in the crosstalk of coagulation and inflammation and study contributions of inflammatory processes to the initiation of coagulation by tissue factor (TF). Our research also broadly addresses open question related to the roles of TF and coagulation protease signaling networks in the integration and modulation of inflammatory stimuli in immune cells. We are interested in the control of macrophage phenotypes by coagulation proteases and their receptors in chronic inflammation and use novel genetic mouse models that selectively delete or alter signaling specificity of components of the hemostatic system in innate immune cell populations. This genetic platform is employed in combination with transcriptional and proteomics approaches for generating fundamentally novel insights into cellular and molecular connections between coagulation and inflammation. We are interested in translational research that deciphers molecular mechanisms of diseases of the cardiovascular system and evaluates clinically relevant interventional proof-of-principle molecular probes in disease models.

Research Interests

• Molecular mechanisms of prothrombotic activation of TF
• Coagulation protease signaling in myelo-monocytic cells
• Protease activated receptor (PAR) signaling specificity in inflammation
• Crosstalk of the hemostatic system with tumor progression and angiogenesis

Third party funding

• Alexander von Humboldt Stiftung
• BMBF 'Clusters4Future' (curATime; P2 curATarget; P9 endoTArget)
• Horizon 2020 - Marie Skłodowska-Curie Innovative Training Network (TICARDIO Research Consortium)
• DFG (CRC 1292: TP02 and TP10)
• DFG TransRegio 156
• DFG TRR 355
• DZHK
• ReALity Innovation Fund (Forschungsinitiative des Landes Rheinland-Pfalz)
• BIS Cardio Consortium
• Iconics Therapeutics, Inc.

Team

We are looking forward to applications from highly motivated scientists.
Find out more (Pdf-file, 64,2 KB).

Selected publications

• Beck S, Öftering P, Li R, Hemmen K, Nagy M, Wang Y, Zarpellon A, Schuhmann MK, Stoll G, Ruggeri ZM, Heinze KG, Heemskerk JWM, Ruf W*, Stegner D*, Nieswandt B*. Platelet glycoprotein V spatio-temporally controls fibrin formation. Nat Cardiovasc Res. 2023 Apr;2(4):368-382. *Shared Authorship
• Garlapati

  V, Molitor M, Michna T, Harms GS, Finger S, Jung R, Lagrange J,

  Efentakis P, Wild J, Knorr M, Karbach S, Wild S, Vujacic-Mirski K,

  Münzel T, Daiber A, Brandt M, Gori T, Milting H, Tenzer S, Ruf W*,

  Wenzel P*. Targeting myeloid cell coagulation signaling blocks MAP

  kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure. J Clin Invest. 2023 Feb 15;133(4):e156436. *Corresponding Author

• Fleischer

  MI, Röhrig N, Raker VK, Springer J, Becker D, Ritz S, Bros M, Stege H,

  Haist M, Grabbe S, Haub J, Becker C, Reyda S, Disse J, Schmidt T, Mahnke

  K, Weiler H, Ruf W*, Steinbrink K*. Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation. J Thromb Haemost. 2022 Dec;20(12):2823-2836. *Corresponding Author

• Bochenek

  ML, Gogiraju R, Großmann S, Krug J, Orth J, Reyda S, Georgiadis GS,

  Spronk HM, Konstantinides S, Münzel T, Griffin JH, Wild P,

  Espinola-Klein C, Ruf W*, Schäfer K*. EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia. JCI Insight. 2022 Jul 22;7(14):e157701. *Shared Authorship

• Müller-Calleja

  N, Hollerbach A, Royce J, Ritter S, Pedrosa D, Madhusudhan T, Teifel S,

  Meineck M, Häuser F, Canisius A, Nguyen TS, Braun J, Bruns K, Etzold A,

  Zechner U, Strand S, Radsak M, Strand D, Gu JM, Weinmann-Menke J, Esmon

  CT, Teyton L, Lackner KJ*, Ruf W*. Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science. 2021 Mar 12;371(6534):eabc0956. *Shared Authorship

• Graf C, Wilgenbus P, Pagel S, Pott J, Marini F, Reyda S, Kitano M, Macher-Göppinger S, Weiler H, Ruf W. Myeloid cell-synthesized coagulation factor X dampens antitumor immunity. Sci Immunol. 2019 Sep 20;4(39):eaaw8405
• Rothmeier AS, Liu E, Chakrabarty S, Disse J, Mueller BM, Ostergaard H, Ruf W. Identification of the integrin-binding site on coagulation factor VIIa required for proangiogenic PAR2 signaling. Blood 2018;131(6):674-685
• Kamikubo

  Y, Mendolicchio GL, Zampolli A, Marchese P, Rothmeier AS, Orje JN, Gale

  AJ, Krishnaswamy S, Gruber A, Østergaard H, Petersen LC, Ruf W*, Ruggeri ZM*. Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex. Blood. 2017 Oct 5;130(14):1661-1670. *Corresponding Author

• Subramaniam S, Jurk K, Hobohm L, Jäckel S, Saffarzadeh M, Schwierczek K, Wenzel P, Langer F, Reinhardt C, Ruf W. Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood. 2017 Apr 20;129(16):2291-2302.
• Gur-Cohen

  S, Itkin T, Chakrabarty S, Graf C, Kollet O, Ludin A, Golan K,

  Kalinkovich A, Ledergor G, Wong E, Niemeyer E, Porat Z, Erez A, Sagi I,

  Esmon CT, Ruf W*, Lapidot T*. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med. 2015 Nov;21(11):1307-17. *Corresponding Author

• Rothmeier AS, Marchese P, Petrich BG, Furlan-Freguia C, Ginsberg MH, Ruggeri ZM, Ruf W. Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J Clin Invest. 2015 Apr;125(4):1471-84.
• Badeanlou L, Furlan-Freguia C, Yang G, Ruf W*, Samad F*. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med. 2011 Oct 23;17(11):1490-7. *Corresponding Author
• Ahamed J, Versteeg HH, Kerver M, Chen VM, Mueller BM, Hogg PJ, Ruf W. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):13932-7
• Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med. 2004 May;10(5):502-9. doi: 10.1038/nm1037.

Reviews

• Mast AE, Ruf W. Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy. J Thromb Haemost. 2022 Jun;20(6):1290-1300.
• Ruf W. Roles of factor Xa beyond coagulation. J Thromb Thrombolysis. 2021 Aug;52(2):391-396.
• Ruf W, Graf C. Coagulation signaling and cancer immunotherapy. Thromb Res. 2020 Jul;191 Suppl 1:S106-S111.
• Madhusudhan T, Ruf W. Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models. Hamostaseologie. 2019. 39(2):164-172. doi: 10.1055/s-0039-1688800.
• Ruf W. ISTH 2017 Berlin revisited. Res Pract Thromb Haemost 2018;2(1):17-18.
• Zelaya H, Rothmeier AS, Ruf W. Tissue factor at the crossroad of coagulation and cell signaling. J Thromb Haemost 2018;16(10):1941-1952.
• Nguyen TS, Lapidot T, Ruf W. Extravascular coagulation in hematopoietic stem and progenitor cell regulation. Blood 2018.
• Ruf W. Proteases, Protease-Activated Receptors, and Atherosclerosis. Arterioscler Thromb Vasc Biol 2018;38(6):1252-1254.
• Langer F, Ruf W. Synergies of phosphatidylserine and protein disulfide isomerase in tissue factor activation. Thromb Haemost. 111, 2014.
• Rothmeier A, Ruf W.  Protease-activated receptor 2 signaling in inflammation. Seminars in Immunopathology. 34:133-49, 2012.
• Ruf W. Chapter 44: Coagulation-Independent Signaling of the Extrinsic Coagulation Pathway. In: Marder, V., Aird, W. C., Bennett, J., Schulman, S., White, G. CC. (Eds.): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 6e. Lippincott Williams & Wilkins. 579-584, 2012.
• Ruf W, Disse J, Carneiro-Lobo TC, Yokota N, Schaffner F.  Tissue factor and cell signalling in cancer progression and thrombosis. J. Thromb. Haemost.  9 S1:306-15, 2011.

Editorials, Comments and other articles

• Koizume S, Kobayashi S, Ruf W, Miyagi Y. Authors' reply to the Letter to the Editor: Tissue factor and its procoagulant activity on cancer-associated thromboembolism in pancreatic cancer. Cancer Sci. 2022 May;113(5):1888-1890
• Subramaniam S, Ruf W, Bosmann M. Advocacy of targeting protease-activated receptors in severe coronavirus disease 2019. Br J Pharmacol. 2022 May;179(10):2086-2099.
• Ruggeri ZM, Ruf W. Is VITT really a HIT. Nat Immunol. 2021 Nov;22(11):1352-1353.
• Ruf W. TRIF turns the switch for DIC in sepsis. Blood. 2020 Apr 2;135(14):1073-1074.
• Ruf W. Translational Research in Thrombosis and Haemostasis. Hamostaseologie. 2019 Jun;39(2):115-116.
• Kiouptsi K, Ruf W, Reinhardt C. Microbiota-Derived Trimethylamine. Circ Res. 2018 Oct 26;123(10):1112-1114.
• Ruf W, Preissner KT. State of the Art 2017. J Thromb Haemost. 2017 Jul;15(7):1239.