GAS6/TAM-SIRT1及其介导的关键通路在心肌缺血再灌注损伤中作用的研究

Nature文章指出：生长停滞特异基因6（GAS6）在决定细胞命运过程中扮演重要角色，GAS6与其受体TAM家族（包括Tyro3、Axl、Mer）结合后可以发挥抗凋亡、促增殖和抑制炎症反应等作用。我们前期发现SIRT1激活介导褪黑素抗心肌缺血再灌注损伤（IRI）作用，还发现：①GAS6敲除可以加重小鼠心肌缺血再灌注损伤（IRI），同时伴随SIRT1表达下调；②褪黑素发挥抗心肌IRI伴随着GAS6表达上调（见工作基础）。以上证据强烈提示：GAS6/TAM通路可能是心肌保护中重要通路，其可以通过调控SIRT1及其下游分子发挥抗心肌IRI作用。本项目拟采用GAS6基因敲除和转基因小鼠和细胞模型，研究证实GAS6/TAM-SIRT1信号通路在心肌IRI中的作用及其上下游关系，同时关注该通路在褪黑素的心肌保护机制中的作用，为寻找全新的抗心肌IRI靶点和开发以褪黑素为基础的心肌保护药物奠定理论基础。

Growth arrest-specific gene 6 (GAS6) is a crucial regulator of cell fate. GAS6 can mediate anti-apoptotic, proliferative and anti-inflammatory effects after banding to TAM family (including Tyro3、Axl、Mer). Our previous study showed that silent information regulator 1 (SIRT1) activation is implicated in cardioprotection of melatonin. Further, our recent studies found: ① GAS6-/- mice was more sensitive to IRI than wild-type mice, with down-regulation of SIRT1 expression; ② Melatonin treatment alleviated myocardial IRI, with up-regulation of GAS6 expression. These clues strongly indicate that GAS6/TAM signaling pathway may play vital roles in cardioprotection, and this effect may be mediated through SIRT1. GAS6+/+ or GAS6-/- cell line and mice will be used in this study to explore the role of GAS6/TAM-SIRT1 signaling pathway in myocardial IRI and its regulatory mechanisms. Additionally, effects of melatonin on GAS6/TAM-SIRT1 signaling pathway will aslo be investigated. This project will draw new molecule targets of anti-myocardial IRI, and provide sufficient theoretical basis for the further development of melatonin-based cardioprotective treatment.