Gas6/MerTk信号通路通过IL-10调控心肌细胞自噬保护脓毒症心肌损伤的机制研究

烧伤脓毒症相关心脏损害治疗棘手且死亡率高。脓毒症时过度的炎症应答会破坏心肌细胞线粒体稳态、导致细胞凋亡。我们前期研究发现脓毒症大鼠心脏组织自噬水平受抑制是细胞凋亡的关键环节，但自噬受损的机制目前尚不明确。我们预实验发现巨噬细胞Mer受体酪氨酸激酶（MerTK）水平异常致Gas6/MerTK信号通路障碍，促进脓毒症大鼠心脏炎症小体激活。在动物模型中抑制MerTK进一步加剧炎症小体水平；而上调MerTK水平减轻炎症水平。自噬是线粒体稳态和炎症小体活化中的关键一环，由此提出科学假设：Gas6/Mertk信号通路调控自噬通路对炎症小体的释放可能在脓毒症相关心脏损伤中发挥重要作用。本课题拟在体外细胞实验和脓毒症大鼠模型中，通过细胞特性和组织病理两方面及相关基因调控明确Gas6/MerTk介导的心肌细胞自噬与炎症小体的激活及三者之间的关系，以期揭示潜在的干预靶点，为脓毒症心肌损伤研究提供新思路。

Burn sepsis related heart injury can be difficult to handle and it has a high mortality rate. Excessive inflammatory response in sepsis disturbing the homeostasis of cardiomyocyte mitochondria will lead to cell apoptosis. Our previous studies have found that the autophagy inhibition in the heart of septic rats is an important role in cell apoptosis, but the mechanism of autophagy impairment is still unclear. Our preliminary experiments have found that the soluble and membrane-bound ratio of the Mer receptor tyrosine kinase (MerTK) and the imbalance of the ligand Gas6 level promote the activation of cardiac inflammasomes in septic rats. In the knockdown MerTK cell model, the inflammatory response is further exacerbated; and the increase of MerTK level promotes the autophagy level of cardiomyocytes. Therefore, we came up with the hypothesis：The Gas6/Mertk signaling pathway modulates the release of inflammasomes by regulating autophagy pathway，which may play an important role in sepsis-related heart injury. This project intends to clarify Gas6/Mertk-mediated cardiomyocyte autophagy and inflammasome activation in vitro cell experiments and sepsis rats models, through cell characteristics and histopathological analysis and gene modulation， in order to reveal potential intervention targets and provide new ideas for the study of septic myocardial injury.