接头分子Cbl与血管再狭窄的防治.ppt

1,Fighting Restenosis:Targeting c-Cbl,Nanping WangInstitute of Cardiovascular SciencePeking University,2,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,3,Gene Therapy-Preclinical Study,Rissanen and Yla-Herttuala.Mol Ther.2007;15:1233-47,4,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).,5,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.,6,c-Cbl Tyrosine Phosphorylation Is Increased in Injured Arteries,7,PDGF Increased c-Cbl Tyrosine Phosphorylation in SMCs,8,A Hierarchical Signaling Cascade from c-Cbl to PI3K/akt/mTOR in SMCs,9,Ablation of c-Cbl Tyrosine Phosphorylation:A Tool to Fight Restenosis?,10,Conditional Expression of c-Cbl Mutant in SMCs,11,c-Cbl-m Suppressed SMC Proliferation and Migration,12,c-Cbl-m Restricted G1/S Progression in SMCs,13,c-Cbl-m Inhibited PI3K/Akt/mTOR Activation in SMCs,14,Constitutive Activation of PI3K or Akt Attenuated the c-Cbl-m Effects,15,16,c-Cbl-m Increased Ubiquitination of PDGF and FGF Receptors,17,Adenovirus-mediated Gene Transfer of c-Cbl-m Inhibits Akt/mTOR Activation in vivo,18,c-Cbl-m Inhibits SMC Proliferation and Migration in vivo,19,c-Cbl-m Inhibits Intimal Hyperplasia in Balloon-injured Arteries,20,Proposed role of c-Cbl in vascular Remodeling,21,Acknowledgment,National Science Foundation of ChinaMajor Grant for Diabetes Research,MOST,Zhihui Tang,Ying Wang,Yanbo Fan,