Molecular mechanisms of fibrin functions at the neurovascular interface

• Applicant: Professor Christian Schachtrup, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2005 to 2007
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 12754829

• Final Report Year: 2008

Final Report Abstract

Changes in the molecular and cellular composition of the central nervous system (CNS) after injury or disease result in the formation of an inhibitory environment that inhibits the regeneration of adult mammalian CNS neurons. Although a dramatic change in the CNS environment after traumatic injury or disease is hemorrhage due to vascular rupture or leakage of the blood-brain barrier (BBB), the potential role for blood proteins in repair processes remains unknown. Here we show that the blood protein fibrinogen is a novel inhibitor of neurite outgrowth that is massively deposited in the spinal cord after injury. We show that fibrinogen acts as a ligand for ß3 integrin and induces the transactivation of Epidermal Growth Factor receptor (EGFR) in neurons. Fibrinogen-mediated inhibition of neurite outgrowth is reversed by blocking either ß3 integrin or phoshorylation of EGFR. Inhibition of Src family kinases (SFK) that mediate the cross-talk between integrin and growth factor receptors rescue the fibrinogen-induced phosphorylation of EGFR. These results identify fibrinogen as the first blood-derived inhibitor of neurite outgrowth and suggest fibrinogen-induced EGFR transactivation on neuronal cells as a molecular link between vascular and neuronal damage in the CNS after injury.

Publications

• (2002) Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1. Diabetes 51: 2922-2928
  Y. Uehara, T. Engel, Z. Li, C. Goepfert, S. Rust, X. Zhou, C. Langer, C. Schachtrup, J. Wiekowski, S. Lorkowski, G. Assmann, A. von Eckardstein
  
• (2003) Vitamin E deficiency reduces surfactant lipid biosynthesis in alveolar type II cells. Free Radical Biol Med 34: 663-673
  F. Guthmann, I. Kolleck, C. Schachtrup, M. Schlame, F. Spener and B. Rüstow
  
• (2004) Functional analysis of peroxisome proliferator response element motifs in genes of fatty acid binding proteins. Biochem J, 382: 239-245
  C. Schachtrup, T. Emmler, B. Bleck, A. Sandqvist, and F. Spener
  
• (2004) L-FABP is exclusively expressed in alveolar macrophages within the myeloid lineage. Evidence for a PPARα-independent expression. Int J Biochem Cell Biol 36: 2052-2063
  C. Schachtrup, T.E. Scholzen, V. Grau, T.A. Luger, F. Spener, and C. Kerkhoff
  
• (2004) Phenotype of palmitic acid transport and of signalling in alveolar type II cells from E/H-FABP double-knock out mice: Contribution of caveolin-1 and PPARg. Biochim BJophys Acta 1636: 196-204
  F. Guthmann, C. Schachtrup, A. Tolle, H. Wissel, B. Binas, H. Kondo, Y. Owada, F. Spener and B. Rüstow
  
• (2005) Expression of livertype fatty acid binding protein in murine lung and its release into serum upon challenge of lung with lipopolysaccharide. Eur J Lipid Sci Technol, 107:145-152
  P. Piumngam, C. Schachtrup, Y. Owada, C. Promptmas, and F. Spener
  
• (2005) Inhibition of TNFalpha in vivo prevents hyperoxia-mediated activation of caspase 3 in type II cells. Respir Res, 6:10
  F. Guthmann, H. Wissel, C. Schachtrup, A. Tolle, M. Rüdiger, F. Spener, B. Rüstow
  
• (2006) Livertype fatty acid binding protein in serum and broncho-alveolar lavage in a model of acute respiratory failure because of surfactant depletion-a possible marker for lung damage? Clin Physiol Funct Imaging, 26:371-375
  R.A. Lachmann, S. Werchan, C. Schachtrup, J.J. Haitsma, F. Spener, B. Lachmann
  
• (2007) Fibrinogen inhibits neurite outgrowth via beta3 integrin-mediated phosphorylation of the EGF receptor. Proc Natl Acad Sci USA, 104: 11814-11819
  Schachtrup, P. Lu, L.L. Jones, J.K. Lee, J. Lu, B.D. Sachs, B. Zheng, K. Akassoglou
  
• (2007) Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis. Curr Med Chem. 14:2925-36
  R.A. Adams, C. Schachtrup, D. Davalos, l. Tsigelny, K. Akassoglou
  
• (2007) p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J Cell Biol, 177: 1119- 1132
  B.D. Sachs, G.S. Baillie, J.R. McCall, M.A. Passino, C. Schachtrup, D.A. Wallace, A.J. Dunlop, K.F. Mackenzie, E. Klussmann, M.J. Lynch, S.L. Sikorski, T. Nuriel, I. Tsigelny, J. Zhang, M.D. Houslay, M.V. Chao, K. Akassoglou