龙牙楤木皂苷调控钙稳态失衡抑制内质网应激介导心肌保护的药效物质基础及分子机制研究

项目名称： 龙牙楤木皂苷调控钙稳态失衡抑制内质网应激介导心肌保护的药效物质基础及分子机制研究

项目编号： No.81473380

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： 徐惠波

作者单位： 吉林省中医药科学院

项目金额： 73万元

中文摘要： 钙稳态失衡是诱导内质网应激（ERS）发生的重要原因。通过调控钙稳态失衡进而抑制ERS介导的细胞凋亡成为药物抗MIRI的新途径。龙牙楤木系五加科楤木属植物，具有活血化瘀的功效。我们从80年代即开始了对龙牙楤木的研究，发现了其治疗冠心病、心绞痛的新用途，已获临床批件，授权了4项专利，发表12篇论文。近期我们首次发现龙牙楤木总皂苷可提高心肌细胞钙瞬变的幅度；提高SERCA活性，降低PLB 和 NCX蛋白表达。减少MIRI所致钙超载，抑制内质网应激诱导的凋亡。本课题拟在此基础上对龙牙楤木总皂苷及其主要活性成分进行基于调控钙稳态失衡抑制ERS介导MIRI保护机理研究，论证其心肌保护作用可能与直接干预SERCA等钙信号传导蛋白的表达抑制ERS，减少心肌细胞的凋亡，影响缺血再灌注时钙及内质网的交互作用，达到二者的稳态平衡有关，并确证其作用的信号通路与靶分子，探索其保护MIRI的药效物质基础及分子机制。

中文关键词： 龙牙楤木；钙稳态；内质网应激；缺血再灌注；细胞凋亡

英文摘要： Disordered calcium homeostasis can lead to endoplasmic reticulum (ER) stress. Therefore, the attenuation of ER stress-induced apoptosis through modulating calcium homestasis may hold therapeutic promise for the treatment of MI/R injury. Aralia elata (Miq) Seem, which belongs to Araliaceae family, has the effects of promoting blood circulation and removing blood stasis. Continuous studies mainly on its cardioprotective effects have been carried out in our laboratory since 1980s. We found its novel use for the treatment of coronary heart disease, which has obtained Drug Clinical Trial Approval Document (Number 2003L01111) from the state Food and Drug Administration (SFDA), authorized 4 patents and published 12 papers. Recently, we for the first time found that total saponins of Aralia elata could increase the amplitude of E[Ca2+]i transients in a concentration-dependent manner, upregulate the expression of SERCA2a and PLB while decrease NCX expression, thereby reducing MIR-induced calcium overload. In this study, we aim to demonstrate that the cardioprotective activities of total saponins and its active components may be closely associated with modulating SERCA and other calcium signal transduction proteins, thereby inhibiting ER stress dependent apoptosis. Through elucidating the interaction between calcium and endoplasmic reticulum during IR injury, to confirm the signaling pathways and target molecules of Aralia elata saponins and explore the effective substance and molecular mechanism against MI/R injury.

英文关键词： Aralia elata;Calcium homestasis;Endoplasmic Reticulum Stress;Ischemia/Reperfusion (I/R) injury;Apoptosis