SIRT1-CREB1-homer1a通路在脑缺血再灌注损伤中的作用及分子机制

Ischemic stroke is one of the most serious human disorders leading to long-term disability and high mortality. However, the definite mechanism to regulate ischemic tolerance of neurons in ischemia/reperfusion injury has not been explored. Our previous studies found that neurons knocking out SIRT1 showed a mass of cell death in OGD injury, and SIRT1 inhibitor reversed the cerebral-protective effect of Melatonin in MCAO and caused increased infarct volume, brain edema and lowered neurological scores. The further studies confirmed that SIRT1 was significantly decreased accompanied by increased Homer1a significantly in neurons of mice in MCAO/R injury, and down-regulating SIRT1 by shRNA in neurons significantly decreased Homer1a expressions in protein and RNA levels. Ingenuity Pathway Analysis (IPA) identified that CREB1 might be the key nucleus transcriptional factor by which SIRT1 regulates Homer1a expression. We suppose that SIRT1-CREB1-Homer1a might be a novel pathway of neuronal self-repair in brain ischemia/reperfusion injury in mouse. To identify the role and reveal a new mechanism of SIRT1 in neuronal ischemic tolerance, SIRT1 KO mice and Homer1a KO mice were brought in and OGD/R and MCAO/R models were used in vitro and in vivo respectively. It is expected to find a new signaling pathway and provide novel drug targets and treatment strategies for ischemic stroke.

缺血性脑卒中常引起较差的预后和神经功能障碍，然而调控神经元缺血耐受的分子机制尚未完全阐明。我们的研究发现：敲除SIRT1的神经元在OGD损伤后细胞死亡的数量显著增加；抑制SIRT1后逆转了褪黑素对MCAO小鼠的保护作用，引起脑组织梗死体积、脑水肿的增加以及神经功能的恶化。进一步的研究发现：MCAO/R损伤后神经元中SIRT1表达明显下降，而homer1a的表达则显著增加；下调SIRT1后homer1a的RNA及蛋白水平也显著下降。IPA的结果提示CREB1可能参与了SIRT1对Homer1a的调节。我们假设，SIRT1-CREB1-homer1a可能是脑I/R损伤中神经元自我调节新的信号通路。依靠现有的SIRT1 KO小鼠及homer1a KO小鼠，以OGD/R和MCAO/R作为脑I/R损伤离体和在体研究模型，研究SIRT1在神经元缺血耐受中的作用和新机制，为脑I/R损伤的治疗提供新的思路