多囊蛋白1调控平滑肌细胞自噬在主动脉夹层形成中的作用及机制

项目名称： 多囊蛋白1调控平滑肌细胞自噬在主动脉夹层形成中的作用及机制

项目编号： No.81471896

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 柴湘平

作者单位： 中南大学

项目金额： 69万元

中文摘要： 主动脉夹层（AD）是一种严重的大血管病变，主动脉中膜退化和平滑肌细胞数量减少在AD形成中起重要作用。临床上发现AD常并存有多囊肾病，多囊肾病发病的关键是PKD1基因缺失，PKD1基因敲除的动物模型常发生主动脉血肿和小夹层等AD前期改变，PKD1编码的多囊蛋白1(PC1)低表达可致血管壁稳定性下降，我们发现PC1在AD血管壁中表达下降。PC1低表达在肾小管上皮细胞可异常激活雷帕霉素靶蛋白（mTOR），活化的mTOR可以抑制自噬促进细胞死亡。我们前期研究发现自噬在AD血管中显著降低，推测：PC1低表达通过活化mTOR抑制自噬促进细胞凋亡是AD发生的机制之一。本课题以转染PKD1+/-和mTOR+/-基因的平滑肌细胞及小鼠为研究对象，建立PC1低表达的细胞和动物模型，探讨AD形成过程中PC1、mTOR表达及自噬变化与平滑肌细胞死亡之间的关系。以PC1、自噬和平滑肌细胞为切入点，探讨AD的形成机制。

中文关键词： 多囊蛋白1；哺乳动物雷帕霉素靶蛋白；自噬；细胞凋亡；血管平滑肌细胞

英文摘要： Aortic dissection(AD) is a life-threaten condition of large vessels lesion. The degeneration and reduction of smooth muscle cells(SMC) in aortic vessels media play an important role of AD formation. In clinical, aorta dissection offen associated with antosomal dominont polycystic kidney disease(ADPKD).ADPKD mostly caused by mutations PKD1, PKD1 knock-out rats can suffer from the early changes of AD, such as hematomas and small dissections. The low expression of PKD1 coded proteins polycystin-1 (PC1) would also lead the stability of vascular wall decreased, and we found that the expression of PC1 is low in AD. In the renal tubular epithelium,it has been showed that the low expression of PC1 can abnormally activate the mammalian target of rapamycin (mTOR)，which can accelerate the cell-death by inhibiting autophagy. Our previous study showed that the autophagy in the AD vascular was greatly inhibited.Thus,we assume that the low expression of PC1 accelerate the cell-death by activating mTOR and inhibiting autophagy may be greatly involved in the AD pathogenesis; and this may be a new mechanism for the AD formation. In the follwing study,the role of PC1,autophagy and SMC in the AD pathogenesis will be systemically investigated.

英文关键词： Polycystin-1;mTOR;Autophagy;apoptosis;VSMC