Nrf2通过负调控NLRP3炎性复合体的活化减轻脑缺血再灌注损伤的作用及机制研究

深入阐明脑缺血再灌注损伤的发病机制并寻找可能的内源性调控因子是神经保护的未来方向。NLRP3炎性复合体活化可以加重脑缺血再灌注损伤，而其上游调控机制不清。Nrf2作为体内最重要的调控氧化应激的转录因子具有保护脑缺血再灌注损伤的作用。结合现有文献报道和前期研究结果，我们首次提出：“ Nrf2作为NLRP3炎性复合体活化的负调控因子，可能通过抑制TXNIP从Trx1/TXNIP复合物中解离出核和/或通过抑制线粒体mPTP的开放从而减少mtDNA释放，最终抑制NLRP3炎性复合体的活化，减轻脑缺血再灌注损伤”。本项目将离体和在体实验结合，采用慢病毒RNA干扰和过表达技术及其他分子生物学方法，探讨Nrf2对NLRP3炎症复合体活化的负调控作用以及Nrf2对Trx1/TXNIP复合物和mPTP/mtDNA的影响。本研究将进一步阐明脑缺血再灌注损伤的发病机制，为脑卒中的防治提供新靶点和新策略。

Further elucidation of the pathogenesisand find out endogenous molecular may provide promising opportunities to prevent cerebral ischemia reperfusion injury. NLRP3 inflammasome can aggravate cerebralischemia reperfusion injury. However, the signaling pathways that lead to the activation of NLRP3 inflammasome by I/R injury have not been fully elucidated. Nrf2 is a critical transcription factor regulating cellular antioxidant. It can protect brain from ischemia reperfusion injury. On this basis, we put forward the hypothesis: “As the negative regulating factor of NLR3 inflammasome activation , Nrf2 could alleviate cerebral ischemia/reperfusion injury by inhibiting TXNIP release from Trx1/TXNIP complex and /or inhibiting the opening of mPTP and mtDNA release into the cytoplasm.” Using RNA interfering and over-expression technology, we will further study the effects of Nrf2 on NLRP3 inflammasome and the relationship between Nrf2 and Trx1/TXNIP, Nrf2 and mPTP/mtDNA both in vitro and in vivo. This study will further elucidate the pathogenesis of cerebral ischemia reperfusion injury, and which may also provide new strategies for the prevention of stroke.