MCPIP-1的去泛素化作用调控增龄性小鼠心房巨噬细胞-心肌细胞间电耦联重塑的作用及机制

增龄是心房颤动（房颤）至关重要的致病因素，心房纤维化和细胞凋亡导致的电传导异常是增龄性房颤发生的主要机制。本课题组前期研究发现老龄房颤犬心房MCPIP-1表达上调，其诱导的心房纤维化和细胞凋亡加剧增龄导致的心房电重构，但机制不明。研究表明，巨噬细胞通过缝隙连接蛋白与心肌细胞电耦联，调节心肌细胞电传导。本课题拟利用心脏特异性过表达MCPIP-1转基因小鼠模型，明确MCPIP-1过表达是否具有加剧增龄性小鼠心房巨噬细胞-心肌细胞电耦联重塑的作用及其机制，揭示MCPIP-1诱导的巨噬细胞极化状态改变在增龄性小鼠心房细胞间电耦联中的重要性；基于siRNA干扰MCPIP-1表达的巨噬细胞与心房肌细胞体外共培养体系，阐明MCPIP-1的去泛素化作用调控心房巨噬细胞-心肌细胞间电耦联的机制，探寻MCPIP-1去泛素化作用的靶点，为增龄性房颤的防治提供新思路和新靶点，具有重要的科学意义和临床转化应用价值。

Aging is the most vital risk factor of atrial fibrillation (AF), the abnormal electrical conduction which caused by fibrosis and myocardial apoptosis is the chief mechanism that contributes to age-associated AF. It has already been demonstrated in our previous studies that the atrial expression level of MCPIP-1 in aged AF dogs increased. Atrial fibrosis and apoptosis induced by MCPIP-1 may aggravate the electrical remodeling caused by aging. But the mechnism remain unclear. Some researches shows that macrophages connect with myocardial cells via connexin and facilitate intercellular electrical coupling. Meanwhile, it plays an important role in regulating electrical conduction between myocardial cells. In this project, transgenic mouse models which are overexpressed MCPIP-1 will be used to determine whether MCPIP-1 have the effect of aggravating age-associated macrophage-myocyte electrical coupling remodeling and to illuminate the mechanism. It also aims to reveal the importance of macrophage polarization status induced by MCPIP-1 in age-associated macrophage-myocyte electrical coupling remodeling.The myocardial cells and macrophages of which MCPIP-1 expressions are interfered by siRNA will be cocultivated to illuminate the mechanism of MCPIP-1 deubiquitination in macrophage-myocyte electrical coupling and to explore the molecular target during this process. All mentioned above will bring new ideas and new targets to benefit the prevent and treatment of age-associated AF. Furthermore, it not only has a crucial scientific significance but a clinical transformation and application value as well.