白藜芦醇对VDAC1的翻译后修饰在心肌缺血再灌注损伤中的作用研究

项目名称： 白藜芦醇对VDAC1的翻译后修饰在心肌缺血再灌注损伤中的作用研究

项目编号： No.81460495

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 廖章萍

作者单位： 南昌大学

项目金额： 47万元

中文摘要： 白藜芦醇抗心肌缺血再灌注损伤作用与防止mPTP开放有关。我们前期研究证实白藜芦醇对mPTP的影响是由线粒体外膜上的VDAC1介导；预实验中又发现p38MAPK通路激动剂和SIRT1抑制剂均可取消白藜芦醇的心肌保护作用。结合文献，我们假设心肌缺血再灌注时，白藜芦醇通过抑制p38MAPK通路减少VDAC1磷酸化，且又通过激活SIRT1途径对VDAC1去乙酰化，两种方式协同调节VDAC1表达与活性，防止mPTP开放，进而保护心肌细胞。为此，拟用基因克隆、RNAi等重组相应蛋白的腺病毒表达载体，构建相应的转基因细胞与动物，将多种细胞分子生物学技术与经典功能学评价方法有机结合，从心肌细胞及整体动物水平，阐明p38MAPK介导的磷酸化和/或SIRT1介导的去乙酰化修饰VDAC1，在白藜芦醇心肌保护的线粒体机制的作用及其意义，为正确诠释、研究开发防治心血管疾病的天然营养素、植物化合物开辟新的思路。

中文关键词： 白藜芦醇；电压依赖性阴离子通道1；翻译后修饰；p38；MAPK；SIRT1

英文摘要： The effect of resveratrol's protection against myocardial ischemia/reperfusion, is tightly related to its inhibition to mitochondrial permeability transition pore (mPTP) opening. As we previously demonstrated, voltage dependent anion channel 1(VDAC1), a channel that located in the outer membrane of mitochondrial, is involved in the effects of resveratrol on mPTP. Our preliminary experiments also found that both agonist of p38 mitogen-activated protein kinase (MAPK) and antagonist of SIRT1 abolish the protective effects of resveratrol. Combined with literature, we presume that resveratrol regulates VDAC1 activity by means of reduces VDAC1 phosphorylation via inhibiting p38 MAPK pathway, and cooperates with deacetylation on VDAC1 by activating SIRT1. mPTP opening is then blocked, and as a final effect, resveratrol protect caridomyocytes from ischemia/reperfusion injury. In this project, we planed to use gene cloning, RNA interference and recombinant adenovirus vector to construct corresponding transgenic cells and aniamals. A variety of molecular biology techniques, combines with classical functional evaluations to make a full illustration about the role of p38 MAPK mediated phosphorylation and/or SIRT1 mediated deacetylation modification of VDAC1 in the mitochondrial mechanism of resveratrol in myocardial protection. The research work provides new ideas to investigate natural nutrients and plant compounds in prevention and treatment of cardiovascular diseases.

英文关键词： resveratrol;VDAC1;post-translation modifications;p38 MAPK;SIRT1