TIGAR在内质网应激-自噬通路介导缺血后适应脑保护中的作用及机制研究

Cerebral ischemia activates the expression of TIGAR gene and endoplasmic reticulum stress (ERS). Excessive ERS will lead to cerebral ischemia injury by inducing autophagy. Cerebral ischemic postconditioning (Postcond) has been shown to reduce cerebral ischemia-reperfusion injury, but the mechanism remains incompletely understood. Our previous studies have found that Postcond protect against cerebral I/R injury by reducing ER stress-induced apoptosis. On this basis，we speculate that the TIGAR gene mediated ER stress–induced autophay pathway may play an important role in postcond-induced neuroprotection. In our study, we established a rat ischemic postconditioning model in vivo and an oxygen/glucose deprivation (OGD) model in primary cultured murine cortical neurons in vitro. We adopt molecular biology method through (1) Overexpress or silence TIGAR (2) intervention ERS (3) Intervention autophagy,to observe ERS protein, TIGAR ,autophagy marker protein expression,to clarify TIGAR -ERS - autophagy pathways involved in the mechanisms of Postcond–induced neuroprotection. To explore that interference TIGAR gene and the endoplasmic reticulum stress inhibitor can be used in the treatment of ischemic stroke, providing a theoretical basis for the treatment of cerebral ischemia.

脑缺血可以激活TIGAR及内质网应激（ERS）表达，过度的ERS诱导细胞自噬，从而导致脑缺血再灌注损伤。缺血后适应可减轻脑缺血再灌注损伤，但其脑保护机制尚不明确，缺血后适应过程中TIGAR与ERS关系也不明确。我们的前期研究发现，缺血后适应通过抑制ERS、减少细胞凋亡而起到脑保护作用。在此基础上我们拟探讨TIGAR-ERS-自噬之间的关系及其在缺血后适应中的作用机制。拟应用大鼠局灶性脑缺血后适应模型及原代培养神经元缺糖缺氧后适应模型，采用分子生物学方法通过（1）过表达或沉默TIGAR（2）干预ERS（3）干预自噬等方法观察后适应中TIGAR、ERS与自噬的变化，阐明TIGAR-ERS-自噬通路的关系及其参与后适应脑保护的分子机制，为靶向TIGAR或ERS抑制剂用于治疗脑缺血奠定理论基础。

脑缺血可以激活TIGAR及内质网应激（ERS）表达，过度的ERS诱导细胞自噬，从而导致脑缺血再灌注损伤。缺血后适应可减轻脑缺血再灌注损伤，但其脑保护机制尚不明确，缺血后适应过程中TIGAR与ERS关系也不明确。我们的前期研究发现，缺血后适应通过抑制ERS、减少细胞凋亡而起到脑保护作用。在此基础上我们拟探讨TIGAR-ERS-自噬之间的关系及其在缺血后适应中的作用机制。拟应用大鼠局灶性脑缺血后适应模型及原代培养神经元缺糖缺氧后适应模型，采用分子生物学方法通过（1）过表达或沉默TIGAR（2）干预ERS（3）干预自噬等方法观察后适应中TIGAR、ERS与自噬的变化，阐明TIGAR-ERS-自噬通路的关系及其参与后适应脑保护的分子机制，为靶向TIGAR或ERS抑制剂用于治疗脑缺血奠定理论基础。