Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,Fighting Restenosis:Targeting c-Cbl,Nanping Wang,Institute of Cardiovascular Science,Peking University,1,Fighting Restenosis:Targetin,Coronary artery disease:a significant health threat afflicting millions of individuals worldwide.,Despite the development of a variety of technologies and catheter based interventions,post-procedure,restenosis,is still a significant concern.,Gene therapy has emerged as a promising approach aimed at modifying cellular processes that give rise to restenosis.,Restenosis,2,Restenosis2,Gene Therapy-Preclinical Study,Rissanen and Yla-Herttuala.Mol Ther.2007;15:1233-47,3,Gene Therapy-Preclinical Study,c-Cbl,Cellular homologue of,retroviral oncogenic protein,v-Cbl,which induces Casitas B-lineage lymphoma.,An,adaptor,protein and an,E3 ubiquitin ligase,.,Tyrosine phosphorylated,in response to various including integrins and activation of receptor tyrosine kinases(PDGFR and FGFR).,4,c-CblCellular homologue of ret,Aim of the Study,To determine the pathophysiological role of c-Cbl in vascular injury response in SMCs,in vitro,and balloon-injured arteries,in vivo,.,5,Aim of the StudyTo determine t,c-Cbl Tyrosine Phosphorylation Is Increased in Injured Arteries,6,c-Cbl Tyrosine Phosphorylation,PDGF Increased c-Cbl Tyrosine Phosphorylation in SMCs,7,PDGF Increased c-Cbl Tyrosine,A Hierarchical Signaling Cascade from c-Cbl to PI3K/akt/mTOR in SMCs,8,A Hierarchical Signaling Casca,Ablation of c-Cbl Tyrosine Phosphorylation:A Tool to Fight Restenosis?,9,Ablation of c-Cbl Tyrosine Pho,Conditional Expression of c-Cbl Mutant in SMCs,10,Conditional Expression of c-Cb,c-Cbl-m Suppressed SMC Proliferation and Migration,11,c-Cbl-m Suppressed SMC Prolife,c-Cbl-m Restricted G1/S Progression in SMCs,12,c-Cbl-m Restricted G1/S Progre,c-Cbl-m Inhibited PI3K/Akt/mTOR Activation in SMCs,13,c-Cbl-m Inhibited PI3K/Akt/mTO,Constitutive Activation of PI3K or Akt Attenuated the c-Cbl-m Effects,14,Constitutive Activation of PI3,15,15,c-Cbl-m Increased Ubiquitination of PDGF and FGF Receptors,16,c-Cbl-m Increased Ubiquitinati,Adenovirus-mediated Gene Transfer of c-Cbl-m Inhibits Akt/mTOR Activation in vivo,17,Adenovirus-mediated Gene Trans,c-Cbl-m Inhibits SMC Proliferation and Migration,in vivo,18,c-Cbl-m Inhibits SMC Prolifera,c-Cbl-m Inhibits Intimal Hyperplasia in Balloon-injured Arteries,19,c-Cbl-m Inhibits Intimal Hyper,Proposed role of c-Cbl in vascular Remodeling,20,Proposed role of c-Cbl in vasc,Acknowledgment,National Science Foundation of China,Major Grant for Diabetes Research,MOST,Zhihui Tang,Ying Wang,Yanbo Fan,21,AcknowledgmentNational Science,