mTOR信号调控血管平滑肌细胞衰老及脂联素的干预作用

项目名称： mTOR信号调控血管平滑肌细胞衰老及脂联素的干预作用

项目编号： No.81501212

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 詹俊鲲

作者单位： 中南大学

项目金额： 17.5万元

中文摘要： 血管衰老能改变多种心血管疾病发生阈值、进程和严重程度，其与血管平滑肌细胞(VSMCs)过多过快衰老相关。新近研究发现雷帕霉素抑制哺乳动物雷帕霉素靶蛋白(mTOR)可显著促进健康长寿但临床转化受阻。申请人的工作将mTOR与血管衰老联系起来，前期研究首次证明：mTOR信号参与调控VSMCs向成骨细胞转分化和钙化，脂联素减缓这一进程；而血管钙化是血管衰老的重要表型。申请人预实验构建了VSMCs复制性衰老及高糖诱导的早衰模型并发现mTOR表达上调，初步发现脂联素降低高糖诱导的早衰VSMCs的mTOR表达、β-半乳糖酐酶活性及染色阳性率。据此提出假说：mTOR参与调控VSMCs衰老；脂联素通过抑制mTOR信号延缓高糖诱导的VSMCs早衰。我们将用VSMCs两种衰老模型和STZ糖尿病小鼠，通过体内外研究验证假说，并初步确定脂联素干预时点。力图为延缓血管衰老提供新靶点，为改善糖尿病性血管衰老提供新方法。

中文关键词： 细胞衰老；血管衰老；哺乳动物雷帕霉素靶蛋白；脂联素；衰老相关疾病

英文摘要： Vascular aging can change the onset thresholds, process and severity of a variety of cardiovascular diseases. Overbalanced or accelerated senescence of vascular smooth muscle cells (VSMCs)is found to be one of the main contributors behind vascular aging. Recent study found that rapamycin can significantly extend lifespan and delay the onset of aging-related deseases via inhibiting the mammalian target of rapamycin (mTOR), but the work on translating it into clinical application is blocked. The applicant intends to explore the link between vascular aging and mTOR. Our preliminary results demonstrate that mTOR regulates the vascular calcification that results from the osteoblastic differentiation of VSMCs. This process can be alleviated by adiponectin.It is well know that vascular calcification is the most important characteristics of vascular aging . The constructed models in pre-experiment showed that mTOR was up-regulated in the replicative senescence of VSMCs and the premature senescence induced by high glucose. The pre-experiments also revealed that adiponectin can down-regulate the expression of mTOR in the premature senescence of VSMCs induced by high glucose, decrease the activity of senescence-associated β-galactosidase, and decrease the staining positive rate. Based on these results, the applicant puts forword the hypothesis: mTOR regulates VSMCs senescence; adiponectin can delay the premature senescence of VSMCs induced by high glucose through inhibiting mTOR. The applicant will test the hypothesis using the two types of VSMCs senescence models and streptozotocin(STZ) -induced diabetic mice in vivo and in vitro, and determine the intervention time of adiponectin. By this project we try to provide new targets for delaying vascular aging, and provide a new method for improving diabetic vascular aging.

英文关键词： cell senescence; vascular aging;mTOR; adiponectin;aging-related diseases