Dectin-2-BCLAF1途径促进心肌缺血再灌注损伤及机制研究

固有免疫相关模式识别受体（PRR）参与心肌缺血/再灌注（I/R）损伤。我们发现I/R损伤心肌中PRR的成员Dectin-2表达增高，Dectin-2通路激活促进炎症、凋亡、自噬异常，加剧心肌I/R损伤。用免疫沉淀-质谱发现并证实，I/R损伤时Dectin-2的新配体-BCL2相关转录因子1（BCLAF1）升高。BCLAF1生理时分布于细胞核，缺氧复氧刺激后BCLAF1迁移至胞浆。高表达BCLAF1使小鼠心肌I/R后心功能减退；使缺氧复氧的心肌细胞炎症、凋亡和自噬异常加重；诱导巨噬细胞炎性反应。心肌I/R损伤时Dectin-2结合并磷酸化BCLAF1。后续将采用野生型和基因修饰小鼠，以体内外实验探讨Dectin-2、BCLAF1及Dectin-2-BCLAF1通路与心肌I/R损伤及疾病时炎症、凋亡、自噬异常的关系，寻找BCLAF1磷酸化位点和与Dectin-2结合功能域，阐明致病机制和途径。

Pattern recognition receptors (PRRs) are closely involved in the process of myocardial Ischemia/Reperfusion (I/R) injury. The present study showed that Dectin-2, a major C-type lectin-like receptors of the PRRs, is highly induced after myocardial I/R injury. Activation of Dectin-2 aggravated myocardial I/R injury via pro-apoptotic activities, pro-inflammatory reaction and abnormal autophagy. In a co-immunoprecipitation-mass spectrometry analysis, we uncovered that Bcl-2-associated transcription factor 1(BCLAF1), a novel Dectin-2 ligand, was significantly elevated. BCLAF1 stayed in nuclear physiologically and migrated to cytoplasm in hypoxia-reoxygenation. Over-expression of BCLAF1 crippled mouse cardiac function after I/R injury, and induced inflammation, apoptosis, and abnormal autophagy in myocytes in normal and hypoxia-reoxygenation status. During hypoxia-reoxygenation, Dectin-2 bound and phosphorylated BCLAF1. In the future study, we will verify the adverse effects of Dectin-2, BCLAF1 and Dectin-2-BCLAF1 pathway in myocardial I/R injury using wide-type and genetically modified mouse model with mechanisms regarding inflammation, apoptosis and abnormal autophagy probed. In addition, phosphorylation sites and interacting domain of BCLAF1 by Dectin-2 will be investigated.