公开(公告)号：EP2002005A1

公开(公告)日：2008-12-17

申请号：EP07710767.0

申请日：2007-03-19

申请人： McGill University

发明人： FOURNIER, Alyson, E. ,  ALABED, Yazan, Z.

IPC分类号： C12N15/12 ,  A61K38/17 ,  A61P25/28 ,  C07K14/47 ,  G01N33/53

CPC分类号： C07K14/48 ,  A61K38/00 ,  C07K14/475 ,  G01N33/6896 ,  G01N2500/04

摘要： The present invention relates to the identification of the cytosolic phosphoprotein CRMP4b as a protein that physically and functionally interacts with RhoA to mediate neurite outgrowth inhibition. siRNA-mediated knockdown of CRMP4 promotes neurite outgrowth on myelin substrates indicating a critical role for CRMP4 in neurite outgrowth inhibition. Disruption of CRMP4b-RhoA binding with a competitive inhibitor attenuates neurite outgrowth inhibition on myelin and aggrecan substrates. Stimulation of neuronal growth cones with Nogo leads to co-localization of CRMP4b and RhoA at discrete regions within the actin-rich central and peripheral domains of the growth cone indicative of a potential function in cytoskeletal rearrangements during neurite outgrowth inhibition. Together these data indicate that a RhoA-CRMP4b complex forms in response to inhibitory challenges in the growth cone environment and regulate cytoskeletal dynamics at distinct sites necessary for axon outgrowth inhibition. Competitive inhibition of CRMP4b-RhoA binding suggests a novel, highly specific therapeutic avenue for promoting regeneration following CNS injury.