创伤致心功能障碍中自噬水平降低的分子机制及干预研究

Due to the lack of characteristic clinical features, myocardial occult injury induced by trauma is often miss-diagnosed. If not promptly treated, the patients were vulnerable to acute myocardial infarction under stress and other incentives.It is thus important to explore the related injury indicators to reduce trauma-induced myocardial injury. Our recent study supported by NSFC demonstrated that cardiac autophagy decreased in trauma rats, and the six possible associated proteins were screened out. On this basis,the aims of the present study were: 1) to dynamicly observe cardiomyocyte autophagy levels, mitochondrial function and cardiac function through molecularbiological techniques, cardiac radionuclide imaging, and analyze the possible significance of decreased cardiac autophagy in cardiac dysfunction induced by trauma; 2) to investigate the effect of the serum cytokines interleukin-1β on the autophagy levels of cultured myocardial cells, and look for the biology indicators related to myocardial injury in post-traumatic serum; 3)to investigate whether interleukin-1β would become the early warning biomarker in trauma-induced myocardial injury. In short, the current study were to prove our hypothesis that interleukin-1β might cause cardiac dysfunction by decreasing myocardial autophagy at the molecular, cellular and whole-animal levels. The early warning biomarker might become new target of improving post-traumatic cardiac function and preventing acute myocardial injury after trauma.

创伤所致隐匿性心肌损伤由于缺乏特征性症状及临床体征极易漏诊，如不及时治疗，患者在应激等诱因作用下极易发生急性心肌梗死。我们前一项基金研究发现，创伤大鼠心肌组织自噬水平的下降早于其心功能的降低，并筛选出6种可能与其相关的血清蛋白。本课题拟在此基础上运用分子生物学、核素成像等技术动态观察创伤大鼠心肌组织自噬水平、线粒体功能及心功能改变之间的关系，探讨心肌组织自噬水平下降在随后心功能降低中的可能意义；通过基因沉默、重组等技术，明确筛选出的细胞因子IL-1β(白细胞介素1β)对培养的心肌细胞自噬水平的影响，寻找与心肌损伤有关的目标蛋白；通过在大鼠创伤模型中运用相应拮抗剂干预，验证IL-1β是否可早期预测创伤致心肌损伤。本课题拟从分子、细胞及整体水平证实假说：作为创伤后早期事件的6种蛋白质中，细胞因子IL-1β(白细胞介素1β)与创伤大鼠心肌组织自噬水平改变有关，进而参与随后的心功能降低。本研究将为寻找与创伤后心肌损伤有关早期预警分子提供新靶点。

创伤所致隐匿性心肌损伤由于缺乏特征性症状及临床体征极易漏诊，如不及时治疗，患者在应激等诱因作用下极易发生急性心肌梗死。我们前一项基金研究发现，创伤大鼠心肌组织自噬水平的下降早于其心功能的降低，并筛选出6种可能与其相关的血清蛋白。本课题在此基础上运用分子生物学、核素成像等技术动态观察创伤大鼠心肌组织自噬水平、线粒体功能及心功能改变之间的关系，探讨心肌组织自噬水平下降在随后心功能降低中的可能意义；通过基因沉默、重组等技术，明确筛选出的细胞因子IL-1β(白细胞介素1β)对培养的心肌细胞自噬水平的影响。通过本课题研究，发现创伤后心肌组织自噬水平下降在随后的心功能降低中发挥着重要作用；通过构建pSUPER-Beclin 1重组载体，发现IL-1β可能通过降低心肌细胞自噬水平进而导致创伤后离体心功能降低，以上结果提示IL-1β有望成为创伤所致继发性心脏损伤的潜在预测和干预靶点。