脑缺血/再灌注时MALT1促神经细胞坏死样凋亡作用及机制

坏死样凋亡是脑缺血/再灌注（I/R）时神经细胞死亡的重要方式之一，本项目预实验首次发现I/R处理大鼠脑组织中MALT1表达上调，伴随A20蛋白水平下降、TAK1磷酸化水平升高、RIPK1/RIPK3/MLKL通路激活。抑制MALT1降低了脑梗死体积，伴随A20水平升高、TAK1及MLKL磷酸化水平降低；抑制肌球蛋白调节轻链(MLC20)磷酸化可阻断I/R诱导的MALT1表达上调。我们率先提出：脑I/R时，MALT1表达上调促进了神经细胞坏死样凋亡，其机制涉及A20水平降低和/或TAK1激活、继而促进RIPK1/RIPK3/MLKL复合物形成；而MALT1表达上调与MLC20磷酸化水平升高有关。利用大鼠脑和神经细胞损伤模型，结合药物干预、基因沉默、基因敲除等手段，本项目拟阐明MALT1通过水解A20和激活TAK1促坏死样凋亡作用机制及其表达调节机制，为寻找防治脑I/R损伤新药提供理论依据。

Necroptosis is considered as an important manner of brain cell death following cerebral ischemia/reperfusion (I/R). The preliminary data of this project showed that in rat model of cerebral I/R, the expression of mucosa-associated lymphoid tissue lymphoma translocation protein-1(MALT1) was increased, accompanied by the decreased expression of A20, enhanced phosphorylation level of transforming growth factor-β-activated kinase 1（TAK1）and activation of receptor interaction protein kinase1/3/mixed lineage kinase domain-like protein (RIPK1/RIPK3/ MLKL) pathway. Inhibition of MALT1 reduced infarct volume, along with increased expression of A20 and decreased the phosphorylation levels of TAK1 and MLKL. The decrease in phosphorylation level of myosin regulatory light chain (MLC20) attenuated the expression of MALT1. Based on these observations, we hypothesize for the first time that the increased MALT1 expression exacerbates neuronal necroptosis following cerebral I/R, which might be related to the reduced A20 expression and TAK1 activation, subsequently following by the formation of necroptotic complex of RIPK1/RIPK3/MLKL, while the expression of MALT1 might be modulated by MLC20. In the I/R or hypoxia/reoxygenation(H/R) injury model, combining the methods of gene silence/knock out and drug interference, etc, we will mainly focus on elucidating the role of MALT1 in enhancing neuronal cell necroptosis through cleaving A20 and activating TAK1 in vivo/vitro and the underlying mechanisms. This project will lay a theoretic foundation and provide the new idea for seeking novel drug targets against cerebral ischemic injury.