丹参酮I通过上调Aagab减少PTEN核转移抑制自噬在缺氧缺血性脑损伤修复中的作用机制

缺氧缺血（HI）引起的神经元死亡是新生儿缺氧缺血性脑病（HIE）的重要病理基础。申请人前期研究报道丹参酮Ⅰ（TsI）有神经元保护作用，但机制不明。近期发表文章发现HI 后PTEN核转移增加与神经元死亡有关，上调Aagab抑制PTEN核转移。预实验又发现TsI可上调 Aagab、减少HI后PTEN核转移、降低SESN2及p-JUN蛋白水平、抑制自噬激活。据此推测：TsI发挥神经元保护作用的可能分子机制是通过上调Aagab减少PTEN核转移抑制p-JUN-SESN2/AMPK通路活化抑制自噬激活。本项目拟探讨：①TsI是否通过抑制自噬激活发挥神经元保护作用，②PTEN核转移是否通过p-JUN-SESN2/AMPK通路激活自噬导致神经元死亡；③TsI是否通过上调 Aagab减少PTEN核转移抑制HI后神经元死亡。旨在阐明TsI发挥神经元保护作用的分子机制，为治疗HIE提供新的靶点和思路。

Neuron death caused by hypoxia ischemia (HI) is the important pathological basis of neonatal hypoxic-ischemic encephalopathy (HIE). Our previous study has reported that tanshinone I (TsI) exists neuroprotective effect. However, the underling mechanisms are poorly understood. Recent study also found that the neuron death induced by HI was related to the increase of PTEN nuclear translocation, and Aagab up-regulation suppressed PTEN nuclear translocation. In addition, our pre-experiment data showed that TsI treatment can up-regulate Aagab, reduce PTEN nuclear translocation induced by HI, decrease SESN2 and p-JUN protein level, and suppress the activation of autophagy. Therefore, we speculate that the possible mechanism of the neuroprotective effect of TsI is to inhibit the activation of autophagy through inhibiting p-JUN-SESN2/AMPK pathway by up-regulating Aagab and decreasing PTEN nuclear translocation. The present project intends to explore: ① TsI exerts neuroprotective effect whether through inhibiting autophagy. ② The neuron death caused by PTEN nuclear translocation whether through activating autophagy by activating p-JUN-SESN2/AMPK pathway. ③ TsI suppress the death of neuron induced by HI whether through up-regulating Aagab to reduce PTEN nuclear translocation. The present study aimed to clarify the molecular mechanisms of the neuroprotective effect of TsI. Knowledge gained from this study may provide new target and clinical therapeutic methods for HIE.