Die Rolle der Notch Signalkaskade bei der Fibroblastenaktivierung in der systemischen Sklerose

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 166222564

• Final Report Year: 2015

Final Report Abstract

Wir konnten im Rahmen des geförderten Projekts zeigen, dass die Notch- Signalkaskade durch vermehrte Expression von Jag1 und Notch1 in SSc-Fibroblasten aktiviert ist. Die Aktivierung der Notch-Signalkaskade induzierte die Differenzierung von ruhenden Fibroblasten in Myofibroblasten und fördert die Kollagensynthese. In vivo war die Aktivierung der Notch-Signalkaskade in Fibroblasten alleine ausreichend, um Fibrose zu induzieren. Im Gegensatz dazu hemmt die pharmakologische oder genetische Hemmung der Notch-Signalkaskade die Fibroblastenaktivierung in vitro und zeigt potente anti-fibrotische Effekte in verschiedenen Tiermodellen der SSc.

Publications

• Induction of apoptosis in circulating angiogenic cells by microparticles. Arthritis Rheum. 2011 Mar 24
  Distler JH, Akhmetshina A, Dees C, Jüngel A, Stürzl M, Gay S, Pisetsky DS, Schett G, Distler O
  
• Inhibition of glycogen synthase kinase 3{beta} induces dermal fibrosis by activation of the canonical Wnt pathway. Ann Rheum Dis. 2011 Aug 25
  Bergmann C, Akhmetshina A, Dees C, Palumbo K, Zerr P, Beyer C, Zwerina J, Distler O, Schett G, Distler JH
  
• Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum. 2011 Feb 10
  Dees C, Zerr P, Tomcik M, Beyer C, Horn A, Akhmetshina A, Palumbo K, Reich N, Zwerina J, Sticherling M, Mattson MP, Distler O, Schett G, Distler JH
  
• Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis. 2011 Mar 30
  Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, Beyer C, Zwerina J, Distler O, Schett G, Distler JH
  
• The transcription Faktor JunD mediates transforming growth Faktor {beta}-induced fibroblast activation and fibrosis in systemic sclerosis. Ann Rheum Dis. 2011 Jul;70(7):1320-6
  Palumbo K, Zerr P, Tomcik M, Vollath S, Dees C, Akhmetshina A, Avouac J, Yaniv M, Distler O, Schett G, Distler JH
  
• Activation of canonical Wnt signalling is required for TGF-β mediated fibrosis. Nature Commun. 2012, Mar 13;3:735
  Akhmetshina A, Palumbo-Zerr K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, Schneider H, Sadowski A, Riener MO, MacDougald OA, Distler O, Schett G, Distler JH
  
• Beta-catenin is a central mediator of profibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis. 2012 May;71(5):761-7
  Beyer C, Schramm A, Akhmetshina A, Dees C, Kireva C, Gelse K, Taketo MM, Distler O, Schett G, Distler JH
  
• Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. 2012 Feb 21
  Horn A, Palumbo-Zerr K, Cordazzo C, Dees C, Akhmetshina C, Tomcik M, Zerr P, Avouac J, Gusinde J, Zwerina J, Roudaut H, Traiffort E, Ruat M, Distler O, Schett G, Distler JH
  
• Inactivation of Fatty Acid Amide Hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid mediated activation of CB1. Ann Rheum Dis. 2012 Aug 22
  Palumbo-Zerr K, Horn A, Distler A, Zerr P, Dees C, Beyer C, Selvi C, Cravatt BF, Distler O, Schett G, Distler JH
  
• Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling. Ann Rheum Dis. 2012 Nov 12
  Distler A, Deloch L, Huang J, Dees C, Lin NY, Palumbo-Zerr K, Beyer C, Weidemann A, Distler O, Schett G, Distler JH
  
• Inhibition of H3 Lys 27 histone methylation activates fibroblasts and einduces fibrosis. Ann Rheum Dis. 2012 Aug 21
  Krämer M, Dees C, Huang J, Schlottmann I, Palumbo-Zerr K, Zerr P, Gelse K, Beyer C, Distler A, Marquez VE, Distler O, Schett G, Distler JH
  
• Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease. Blood. 2012 Aug 22
  Zerr P, Palumbo-Zerr K, Distler A, Tomcik M, Vollath S, Munoz LE, Beyer C, Dees C, Egberts F, Tinazzi I, Del Galdo F, Distler O, Schett G, Spriewald BM, Distler JH
  
• Inhibition of hedgehog signaling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis. 2012 Mar 8
  Horn A, Kireva T, Palumbo-Zerr K, Dees C, Tomcik M, Cordazzo C, Zerr P, Akhmetshina A, Ruat M, Distler O, Beyer C, Schett G, Distler JH
  
• Inhibition of sumoylation prevents experimental fibrosis. Ann Rheum Dis. Ann Rheum Dis. 2012 Aug 17
  Khodzhigorova A, Distler A, Dees C, Lang V, Sadowski A, Schneider H, Beyer C, Gelse K, Distler O, Schett G, Distler JH
  
• Pomalidomide is effective for prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. Ann Rheum Dis. 2012 Aug 17
  Weingärtner S, Zerr P, Tomcik M, Palumbo-Zerr K, Distler A, Dees C, Beyer C, Shankar SL, Cedzik D, Schafer PH, Distler O, Schett G, Distler JH
  
• Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis. 2012 Jun;71(6):1019-26
  Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, Hirth- Dietrich C, von Degenfeld G, Sandner P, Distler O, Schett G, Distler JH
  
• Activation of pregnane X receptor inhibits experimental dermal fibrosis. Ann Rheum Dis. 2013 Jan 4
  Beyer C, Skapenko A, Distler A, Dees C, Reichert H, Munoz L, Leipe J, Schulze-Koops H, Distler O, Schett G, Distler JH
  
• Blockade of canonical Wnt signaling ameliorates experimental dermal fibrosis. Ann Rheum Dis. 2013 Apr 17
  Beyer C, Reichert H, Akan H, Mallano T, Schramm A, Dees C, Palumbo-Zerr K, Lin N-Y, Distler A, Gelse K, Varga J, Distler O, Schett G, Distler JH
  
• The Wnt antagonists DKK1 and SFRP1 are downregulated by Promoter Hypermethylation in Systemic Sclerosis. Ann Rheum Dis. 2013 May 22
  Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin N-Y, Beyer C, O Distler O, Schett G, Distler JH
  
• Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability. Ann Rheum Dis. 2014 Jan 20
  Distler A, Lang V, Del Vecchio T, Huang J, Zhang Y, Beyer C, Lin NY, Palumbo-Zerr K, Distler O, Schett G, Distler JH