生长因子NRG-1通路在心肌缺血/再灌注损伤内质网应激中的作用和分子机制

项目名称： 生长因子NRG-1通路在心肌缺血/再灌注损伤内质网应激中的作用和分子机制

项目编号： No.81200121

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 方珊娟

作者单位： 首都医科大学

项目金额： 23万元

中文摘要： 内质网应激（ERS）是影响心肌缺血再灌注损伤（IRI）的重要因素。生长因子NRG-1（Neuregulin-1，NRG-1)与心肌细胞膜上的配体ErbB结合，在心肌细胞应激事件中起重要的保护作用。前期研究中，我们发现NRG-1能减轻在体大鼠缺血再灌注心肌细胞的凋亡、缩小心梗面积，其具体下游机制尚不明确。本实验应用分子生物学、激光共聚焦等技术，从整体和细胞两个层次，证实上调NRG-1/ ErbB通路抑制心肌IRI，抑制ERS和ERS相关凋亡，改善内质网钙处理能力；而抑制NRG-1/ErbB通路则起相反的作用。在细胞层次上，进一步探讨NRG-1抗心肌细胞IRI的保护作用依赖于ERS途径及内质网相关的钙稳态。证明NRG-1/ErbB通路是内源性抗心肌IRI的保护通路，其机制涉及内质网应激介导的细胞凋亡和细胞内钙稳态。本课题将从新的视角阐明心肌IRI的分子机制，并为急性心肌梗死的防治提供新靶点。

中文关键词： Neuregulin-1；缺血再灌注损伤；内质网应激；凋亡；心脏

英文摘要： Cardiac endoplasmic reticulum stress (ERS) contributes to myocardial ischemia/reperfusion injury (IRI). Neuregulin-1 (NRG-1), the ligand of the myocardial ErbB receptor, is a protein mediator with regulatory actions on the heart. Our previous study demonstrates NRG-1 protects hearts against myocardial IRI including reducing cardiac cell apoptosis and limiting the size of myocardial infarction. However, the mechanism of this protection is still unclear. This study is to prove the activation of NRG-1/ErbB protects the myocytes against IRI by attenuating ERS and decreasing cell apoptosis associated with ERS, by enhancing the processing capacity of calcium of endoplasmic reticulum in vivo and in vitro by using techniques of molecular biology and laser copolymerization. And inhibiting NRG-1/ErbB will have the opposite action. We will further detect that the protection of NRG-1 against myocardial IRI is through a mechanism depended on ERS associated cell apoptosis and intracellular calcium homeostasis. This project will clarify molecular mechanism in a new view and will find a new target point for the prevention and treatment of acute myocardial infarction.

英文关键词： Neuregulin-1；Ischemia/reperfusion injury；Endoplasmic reticulum stress；Apoptosis；Heart