Wnt信号通路介导老龄心肌缺血损伤的分子机制及其临床意义

项目名称： Wnt信号通路介导老龄心肌缺血损伤的分子机制及其临床意义

项目编号： No.81470468

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： 马依彤

作者单位： 新疆医科大学

项目金额： 72万元

中文摘要： 老龄是缺血性心脏病发病的高危因素，我们前期研究发现老龄心肌中MMP-9的过度表达和炎性细胞浸润增强是缺血性心脏破裂和急性泵衰竭的重要原因，且老龄心肌中Wnt通路较年轻心肌显著激活，但机制不清楚。研究表明FrzA基因的过表达抑制Wnt通路的激活能减轻年轻小鼠心脏破裂的发生率、改善心功能。据此，本项目拟采用携带FrzA基因的双链重组AAV-9载体，通过体外心肌细胞转染实验，明确FrzA对Wnt信号通路关键靶基因调控，揭示Wnt通路激活介导心肌细胞缺血损伤的分子机制。基于老龄鼠体内外源导入FrzA干预实验，探讨Wnt信号转导通路在老龄急性心肌缺血损伤中的作用机制，确定外源FrzA作为心肌缺血损伤治疗靶标的效用；验证临床样本FrzA作为新的心肌缺血损伤诊断分子标志物的可行性和有效性，为老龄缺血性心脏疾病的基因治疗，发现新的临床干预和随访靶标奠定基础。

中文关键词： 缺血性心脏病；老龄；Wnt信号通路；心肌缺血损伤；9型相关病毒

英文摘要： Aging is a risk factor for ischemic heart disease, our previous study found that overexpression of cardiac MMP-9 in aging mice and enhanced inflammatory cell infiltration are important causes of ischemic cardiac rupture and acute pump failure. Wnt pathway in aging myocardial was significantly activated than that in younger myocardial, but the mechanism is unclear. Studies showed that the over-expression of FrzA gene to inhibit Wnt pathway activation can reduce the incidence of cardiac rupture and improve heart function in younger mice. Accordingly, the project intends to use double strand recombinant AAV-9 vector carrying FrzA gene, with cardiomyocytes transfection experiments in vitro, we can clarify the regulation effects of critical target gene of FrzA on Wnt signaling pathway and reveal the molecular mechanisms of crosis and apoptosis of cardiomyocytes mediated by Wnt pathway activation. Based on intervention experiments of in vivo exogenous import of FrzA in aged mice, we can explore the molecular mechanisms of Wnt signal transduction pathway mediated ischemic injury in aging myocardial to determine utility of exogenous FrzA as the therapeutic target for myocardial ischemia. The feasibility and effectiveness of FrzA as new molecular diagnostic markers for myocardial ischemic injury was verified in clinical samples. The discovery will lay the foundation for gene therapy for aging ischemic heart disease and new targets for clinical intervention and follow-up.

英文关键词： ischemic heart disease;aged;Wnt signaling pathway;ischemia heart injury;adeno-associated type 9