Molecular mechanisms of fibrin functions at the neurovascular interface
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
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F. Guthmann, I. Kolleck, C. Schachtrup, M. Schlame, F. Spener and B. Rüstow
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C. Schachtrup, T.E. Scholzen, V. Grau, T.A. Luger, F. Spener, and C. Kerkhoff
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F. Guthmann, C. Schachtrup, A. Tolle, H. Wissel, B. Binas, H. Kondo, Y. Owada, F. Spener and B. Rüstow
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P. Piumngam, C. Schachtrup, Y. Owada, C. Promptmas, and F. Spener
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F. Guthmann, H. Wissel, C. Schachtrup, A. Tolle, M. Rüdiger, F. Spener, B. Rüstow
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R.A. Lachmann, S. Werchan, C. Schachtrup, J.J. Haitsma, F. Spener, B. Lachmann
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Schachtrup, P. Lu, L.L. Jones, J.K. Lee, J. Lu, B.D. Sachs, B. Zheng, K. Akassoglou
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R.A. Adams, C. Schachtrup, D. Davalos, l. Tsigelny, K. Akassoglou
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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
