Pin1激活p53线粒体转位在热打击诱导血管内皮细胞凋亡中的分子机制

项目名称： Pin1激活p53线粒体转位在热打击诱导血管内皮细胞凋亡中的分子机制

项目编号： No.81501690

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： 古正涛

作者单位： 南方医科大学

项目金额： 18万元

中文摘要： 我们前期研究发现，在热打击诱导VEC细胞凋亡中，ROS通过诱导p53快速线粒体转位激活线粒体凋亡信号（p53转录非依赖信号）。既往研究表明:1、p53转录后单泛素化修饰反应是其线粒体转位的关键；2、Pin1可通过特异性结合p53磷酸化位点，调控p53泛素化修饰反应。由此假设，在热打击诱导ROS-p53转录非依赖凋亡信号中，Pin1作为中间环节调控p53线粒体转位。利用过表达和RNAi上调和下调pin1表达、直接位点突变方式阻断p53核表达以及p53与Pin1的结合位点、MnTBAP阻断ROS信号传导，采用Pin1和p53基因敲除鼠，从动物和细胞水平，正反两方面阐明热打击诱导内皮细胞损伤中，ROS通过中间环节Pin1激活p53转录非依赖信号的分子机制。项目研究有助于深刻认识中暑热打击早期血管病变的作用机制，为临床有针对性预防中暑热打击病情进展以降低死亡率和后遗症发生率提供实验依据。

中文关键词： 热打击；血管内皮细胞；pin1；p53线粒体转位；细胞凋亡

英文摘要： Our preliminary study has revealed that heat stress-induced VEC cell apoptosis is associated with translocation of p53 to mitochondria induced by ROS(Transcription-independent p53 apoptosis). Previous studies have suggested that: 1. One important post-translational modification regulating mitochondrial translocation of p53 is monoubiquitination.2. through isomerization of phosphorylated p53, Pin1 promotes its ubiquitylation. Based on these studies, we presumed that pin1 regulate Mitochondrial p53 Translocation during ROS-p53 transcription-independent apoptosis activated by heat stress. Using overexpression or RNAi technique to up- or down-regulate pin1 expression and point mutation directly to block nuclei expression of p53 and the binding-site of p53 and pin1,as well as MnTBAP to block ROS signal transduction, also with pin1 and p53 gene knock out mice, The objective of this study was to analyze The molecular mechanism of Mitochondrial p53 Translocation activated by pin1 during heat stress induced endothelial cell apoptosis. So that we can profound understanding of the mechanism of endothelial dysfunction induced by heat stress and hope to reduce the mortality and morbidity of heatstroke.

英文关键词： heat stress;vascular endothelial cell;pin1;mitochondrial p53 Translocation;cell apoptosis