补体C3a在心肌梗死后心脏重塑中的作用机制研究

项目名称： 补体C3a在心肌梗死后心脏重塑中的作用机制研究

项目编号： No.81500265

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张聪聪

作者单位： 首都医科大学

项目金额： 18万元

中文摘要： 冠心病心肌梗死后，活化的肌成纤维细胞产生细胞外基质替代梗死心肌完成心室重塑，心脏炎症微环境可调控细胞外基质合成和降解的平衡维持心脏功能。补体C3a通过受体C3aR调节多种细胞功能参与炎症性疾病的病理生理过程。前期研究发现，梗死心脏中C3aR表达增加，C3aR缺失导致梗死早期室壁破裂率增加和生存率下降，心脏中中性粒细胞浸润增加，但其具体调控机制尚不清楚。据此，提出科学假设：补体C3a-C3aR相关信号通路抑制中性粒细胞的动员和招募，避免其对细胞外基质的降解，在心梗早期心脏重塑中发挥保护作用。我们拟以前降支结扎复制小鼠心肌梗死，使用C3aR敲除小鼠探讨补体C3a-C3aR通路对梗死后心脏重塑和炎症微环境的影响，结合骨髓移植实验、中性粒细胞祛除实验和体外细胞共培养等方法明确补体C3a调控的炎症微环境在心梗后心脏重塑中的分子机制，从而发现心肌梗死室壁破裂等致死性并发症的预防治疗靶点。

中文关键词： 心脏重构；炎症微环境；补体系统；中性粒细胞；细胞外基质

英文摘要： Cardiac remodeling after myocardial infarction includes the replacement of the necrotic area with extracellular matrix secreted by activated cardiac fibroblasts and the clearance of necrotic cells and matrix debris. Cardiac inflammation micro-environment regulates the balance of synthesis and degradation of extracellular matrix. Complement component C3a, as the regulator of cell function, participated in the development of inflammatory diseases. We have previously found that the expression of C3aR increased in infarct heart, there were increased cardiac rupture and decreased survival ratio in C3aR deficiency heart, accompanied with more infiltrated neutrophils, but the regulation mechanism is still unknown. In this study, we will use the C3aR deficiency mice to determine the role of C3a-C3aR pathway in inflammation environment and cardiac remodeling, use bone marrow transplantation, neutrophils depletion and in vitro cell co-culture experiments to clarify the key molecular regulation mechanism of cardiac remodeling after myocardial infarction, which will provide novel target to the prevention of fatal complications such as cardiac rupture.

英文关键词： cardiac remodeling;inflammation microenvironment;complement system;neutrophils;extracellular matrix