雌激素受体与SDF-1α/CXCR4信号通路交互作用调节骨髓源性内皮祖细胞修复梗死心肌的分子机制研究

项目名称： 雌激素受体与SDF-1α/CXCR4信号通路交互作用调节骨髓源性内皮祖细胞修复梗死心肌的分子机制研究

项目编号： No.81200093

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： 李海清

作者单位： 上海交通大学

项目金额： 24万元

中文摘要： 内皮祖细胞(EPC)生物学功能受损是女性绝经后冠心病发病率快速上升及心梗后预后差的重要原因。本项目在我们前期观察到雌激素(E2)通过雌激素受体(ER)上调CXCR4表达促进EPC归巢修复梗死心肌的基础上，培养卵巢切除小鼠骨髓源性EPC，分析其在E2诱导下优势表达的ER亚型(α或β)；应用RNAi技术建立优势ER亚型沉默表达的EPC(EPCi),分析其SDF-1α/CXCR4-JNK、pERK1/2表达及细胞的生物学功能；应用SDF-1α和/或CXCR4拮抗剂AMD3100作用于EPC或EPCi，分析其对优势ER亚型的调节、pERK1/2表达及细胞生物学功能；最后研究优势ER亚型和SDF-1α/CXCR4信号通路的交互作用及其调节EPC修复梗死心肌的机制。该研究将为绝经女性冠心病的防治和提高干细胞移植治疗缺血性心脏病的效果提供新的理论基础及治疗策略。

中文关键词： 雌激素受体；内皮祖细胞；基质细胞衍生因子-1；信号通路；心肌梗死

英文摘要： Impaired biological capacity of endothelial progenitor cells (EPC) is the leading cause which is responsible for rapid increasing incidence of coronary heart disease and worse prognosis in postmenopausal women. Based on the findings that estradiol (E2) enhances the homing of EPC-induced cardiac repair by up-regulating CXCR4 expression via estrogen receptors (ER) pathway, we will firstly culture bone marrow-derived EPC from ovariectomized mice and detect the E2 inducible ER subtype of predominant expression. Secondly, EPC of silent expression of predominant ER subtype (EPCi) with RNA interference technology will be established, the expression of SDF-1α/CXCR4-JNK and pERK1/2 signaling will be examined, and the biological capacity will be detected. Furthermore, after being preconditioned with SDF-1α and/or CXCR4 inhibitor AMD3100, EPC and EPCi will be investigated to analyse the expression of predominant ER subtype and pERK1/2 and biological activity. Finally, we will investigate the effects of predominant ER subtype and SDF-1α/CXCR4 signaling crosstalk on modulating EPC-mediated cardiac repair after acute myocardial infarction.This project will provide new theory and therapeutic strategy for prevention and treatment of coronary heart disease in postmenopausal women and improving the outcomes of treatment of ischem

英文关键词： estrogen receptors；endothelial progenitor cells；stromal cell derived factor-1；signaling pathway；myocardial infarction