预缺血上调内源性缓激肽释放酶表达及神经保护作用的机制

In acute cerebral ischemia, national first sorts drug tissue kallikrein (TK) administered by intravenous injection has been made more positive clinical outcomes. Many studies have shown that exogenousTK prevents neurons from hypoxia/reoxygenation injury. In present study, we will explore the molecular mechanisms underly the expression and regulation of endogenous TK by means of ischemia model. We will first determine cerebral ischemic preconditioning up-regulate expression and regulation of endogenous TK by regulating the the histone methylation and histone deacetylation. Next we will detect that the up-regulation of endogenous TK plays a neuroprotective role in cerebral ischemia/reperfusion (I/R) injury. Then we will show that the up-regultion of endogenous TK activates the β-arrestin-2 assembled B2R/Raf/MEK1/2 signaling module and the ERK1/2, involving the mitochondrial pathway and the nuclear pathway, to protect neurons from cerebral ischemia/reperfusion injury. Our study will provide new therapeutic targets and directions for the prevention and treatment of cerebral ischemia.

国家一类新药组织型缓激肽释放酶(tissue kallikrein, TK)，急性期通过静脉注射给药已经取得较为肯定的临床疗效；大量前期研究结果也表明外源性TK显著减轻缺糖缺氧诱导的神经元损伤。本课题借助于预缺血处理探讨内源性TK的表达及其调控机制。首先明确预缺血和缺糖缺氧通过组蛋白甲基化和乙酰化修饰上调内源性组织型激肽释放酶的mRNA和蛋白的表达；其次揭示预处理诱导的内源性TK上调 参与预缺血诱导的神经元保护作用；紧接着阐明预处理诱导的内源性TK上调通过β-arrestin-2 介导B2R/Raf/MEK1/2 信号转导模块组装，激活其底物ERK1/2及其下游的线粒体通路和细胞核通路的神经保护作用机制。阐明这一机制将为缺血性卒中的预防和治疗提供新的药物靶点和治疗方法。

在急性脑缺血中，通过静脉注射给予国家一级新药组织激肽释放酶（TK）已取得更积极的临床结果。许多研究表明，外源性TK可以防止神经元缺氧/复氧损伤。在本研究中，我们通过缺血模型探索了外源TK表达和调控的分子机制。并且我们通过调节组蛋白甲基化和组蛋白去乙酰化来确定脑缺血预处理上调内源性TK的表达，其在脑缺血/再灌注（I / R）损伤中起神经保护作用。此外，目前的研究调查内源性TK的上调激活β-arrestin-2组装的B2R / Raf / MEK1 / 2信号模块和ERK1 / 2，涉及线粒体途径和核途径，以保护神经元免受脑缺血/再灌注损伤。也许我们的研究可以为预防和治疗脑缺血提供新的治疗靶点和方向。