Sestrin2/AMPK信号通路调控新生鼠缺氧缺血脑损伤细胞自噬的新机制

项目名称： Sestrin2/AMPK信号通路调控新生鼠缺氧缺血脑损伤细胞自噬的新机制

项目编号： No.81501304

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈洪菊

作者单位： 四川大学

项目金额： 18万元

中文摘要： 细胞自噬在新生鼠缺氧缺血脑损伤(HIBD)中起重要作用。近年发现调控自噬的重要因子单磷酸腺苷活化蛋白激酶(AMPK)活化后，可抑制哺乳动物雷帕霉素靶蛋白(mTOR)而激活自噬。我们前期研究发现新生鼠HIBD后，细胞自噬及凋亡的激活与mTOR活性下降有关。但是，AMPK/mTOR通路是否参与调控自噬及凋亡激活？其可能的上下游信号分子是什么？新近发现的肿瘤中可调控AMPK的信号传导蛋白Sestrin2是否参与调节AMPK/mTOR？是否与AMPK上游肝酶B1(LKB1)及mTOR关键自噬下游Unc-51样激酶1(ULK1)相互联系？相关信号机制尚不清楚。本课题将建立新生鼠HIBD模型及体外神经元缺氧缺血模型，研究Sestrin2/LKB1/AMPK/mTOR/ULK1各因子表达，用信号通路抑制或增强方法，揭示Sestrin2/AMPK通路调控自噬促进神经保护的新机制，为HIE临床治疗提供新思路

中文关键词： 新生鼠；缺氧缺血；脑损伤；细胞自噬；信号传导

英文摘要： Cellular autophagy plays an important role in neonatal rats with hypoxic-ischemic brain damage (HIBD). Recent studies found that the important autophagy regulator, adenosine monophosphate-activated protein kinase (AMPK), once activated by upstreams, could inhibit the mammalian target of rapamycin (mTOR) and then activate autophagy. Our previous study found that in neonatal rats after HIBD, activation of autophagy and apoptosis were associated with mTOR inhibition. However, whether AMPK/mTOR signaling pathway is involved in the activation of autophagy and apoptosis? What are the possible up and downstream target proteins in this signal transduction? Whether the recently identified signaling molecular Sestrin2, which can up-regulate AMPK in tumor cells, participates in the AMPK/mTOR pathway regulating? Whether Sestrin2 interacts with the AMPK upstream liver kinase B1 (LKB1) and mTOR key autophagic downstream Unc-51 like kinase 1 (ULK1)? The related signal mechanisms are largely unclear. This topic will establish HIBD model in neonatal rats and hypoxic-ischemic neuronal model in vitro, to detect the expression changes of each factor of Sestrin2/LKB1/AMPK/mTOR/ULK1 pathway. We also inhibit or enhance the main pathway factors, to reveal the mechanisms of modifing this Sestrin2/AMPK related signaling pathway in autophagy regulation, to promote certain neuroprotection. We believe that our research will supply new insights in clinical treatment for HIE.

英文关键词： neonatal rats;hypoxia-ischemia;brain damage;cellular autophagy;signal transduction