SH2B3衔接蛋白对心肌梗死后心室重构的作用及其机制的研究

Left ventricular remodeling after myocardial infarction is a complex process involving multiple factors, in which immune inflammatory response plays a key role.SH2B3 is a kind of adaptor protein which expressed in T/B lymphocytes、 macrophages, and acts as a negative regulator of these immune cells.In our previous study，we have found that the myocardial infarction area of SH2B3-knockout mouse is smaller than WT mouse, the degree of cardiac hypertrophy and fibrosis after myocardial infarction is also reduced.The survival rate of SH2B3-knockout mouse is obviously improved. So we suspect that，SH2B3 may play a very important role in the ventricular remodeling after myocardial infarction. In vitro, firstly，we primary culture myocardial cells of SH2B3-knockout and SH2B3-transgenic mice, studying the role of SH2B3 in inflammation and apoptosis, and exploring the mechanisms. Secondly，we study the role of SH2B3 in the biological characteristics of the macrophage and T/B lymphocyte immune cells. In vivo, we use SH2B3-knockout and SH2B3-transgenic mice to build the model of acute myocardial infarction, studying the impact of SH2B3 on ventricular remodeling after myocardial infarction. What we do in this project will provide a new therapeutic target and provide theoretical basis for the new treatment strategies.

心肌梗死后的心室重构是一个复杂的多因素参与调节的过程，免疫炎症反应在其中发挥着关键性作用，SH2B3是表达在T/B淋巴细胞、巨噬细胞上的衔接蛋白，并负性调控这些免疫细胞。我们的前期研究发现，SH2B3基因敲除后，小鼠心梗面积减小，心梗后的心肌肥厚、纤维化程度降低，生存率明显提高。但SH2B3在心肌梗死后心室重构中的作用国内外尚未见报道。本项目通过研究SH2B3对心肌细胞凋亡、炎症因子以及对巨噬细胞、T/B淋巴细胞等免疫细胞生物学特性的影响，探讨SH2B3对心肌梗死后心室重构的作用机制，并利用SH2B3基因敲除和心脏特异性转基因小鼠在体研究SH2B3对心肌梗死后心室重构的影响，系统阐明SH2B3对心肌梗死后心室重构的作用以及可能的分子机制，为防治心肌梗死后心室重构提供新的治疗靶点，为进一步研究新的治疗策略提供理论依据。

心肌细胞缺血再灌注（ischemia/reperfusion, I/R）损伤为制约心肌梗死后血运重建的关键因素之一。SH2B3衔接蛋白在多种信号传递中起到重要调控作用，而其在心梗后心肌细胞I/R损伤中扮演何种角色尚不明确。本研究发现，心梗I/R模型中，心肌细胞SH2B3表达显著上升。此后，本研究构建基因编辑模型探讨该蛋白在上述病理生理过程中作用。在SH2B3敲除鼠中建立I/R模型，可见与野生型相比，心肌梗死、心功能异常、炎症及凋亡均显著上升。与此同时，心肌特异性过表达SH2B3对上述I/R诱导心肌损害起显著保护性作用。信号分子Akt的活化是SH2B3蛋白影响I/R诱导心肌损害的机制之一，且信号分子ERK1/2和STAT3并不参与上述病理生理过程。Akt抑制剂LY294002的运用进一步证明了Akt活化参与了SH2B3蛋白介导的心肌保护性效应。综上，本研究为心肌细胞I/R损伤的诊断和治疗提供新的靶点。