SWELL1依赖其LRRD结构域抑制STAT3心肌保护信号在MI/R损伤中的作用及机制研究

MI/R损伤可导致心肌细胞凋亡。容积敏感性外向整流型氯离子通道(VSOR Cl-通道)与心肌细胞凋亡密切相关，然而VSOR Cl-通道的蛋白构成以及其在MI/R损伤中的作用机制始终未能明确。SWELL1是近年确认的VSOR Cl-通道构成蛋白。我们前期发现：SWELL1敲低可减轻心肌细胞缺氧/复氧损伤且SWELL1抑制心肌细胞STAT3信号。该预实验结果为研究VSOR Cl-通道在MI/R损伤中的作用和机制提供了依据。因此，本项目拟利用已构建的心肌细胞特异性SWELL1敲除小鼠，结合离体细胞与整体动物实验，明确SWELL1在MI/R损伤中的作用，并探究其依赖LRRD结构域形成SWELL1/Grb2/Caveolin1蛋白复合体抑制STAT3信号的精准分子机制。本项目的实施可望从离子通道功能蛋白的角度揭示MI/R损伤导致心肌细胞凋亡的新机制，为临床防治MI/R损伤提供新的理论依据与干预靶点。

Myocardial ischemia/reperfusion (MI/R) injury causes cardiomyocyte apoptosis. Volume sensitive outwardly rectifying chloride (VSOR Cl-) channel plays an important role in cardiomyocyte apoptosis, however the underlying mechanisms remain largely unknown. SWELL1 is recently identified as an essential protein component of VSOR Cl- channel. We found that SWELL1 knockdown ameliorated hypoxia/reoxygenation-induced cardiomyocyte apoptosis. Furthermore, SWELL1 inhibited STAT3 signaling in dependent of its c-terminal leucine rich repeat domain (LRRD). These preliminary data lead to a strong speculation that SWELL1 plays a detrimental role in MI/R injury probably via inhibiting STAT3 cardioprotection. Therefore, utilizing cardiac specific SWELL1 knockout mice, we aim to investigate the role of SWELL1 in MI/R injury. Moreover, we also aim to clarify whether SWELL1 inhibits STAT3 signaling via the SWELL1-LRRD/Grb2/Caveolin1 complex. This project will provide novel mechanisms and therapeutic targets for clinical MI/R prevention and treatment.