TMEM30A/STAT通路对脑卒中后缺血半暗带组织神经保护中的作用及相关机制研究

血管再通治疗的根本在于存在可挽救的缺血半暗带组织，但是半暗带中是否存在自我保护机制以及临床应用尚不明确。近期研究发现，受损神经元具有多种实现自我保护的机制，这种内源性保护方式可能是干预的新靶点。我们前期发现恒河猴及大鼠脑卒中模型的半暗带组织TMEM30A（跨膜蛋白30A）表达升高。最新文献提示TMEM30A可能通过STAT通路发挥保护作用，但其对半暗带组织的作用尚未见报道。本课题依托大鼠和恒河猴缺血半暗带组织以及体外细胞模型，确定TMEM30A在缺血后表达升高的细胞来源；应用过表达、干扰技术及免疫沉淀等技术，经体外和在体模型，明确TMEM30A发挥保护作用的机制；采用多种影像学方法、电生理学技术，同时应用高血压大鼠、神经元特异性敲除小鼠，量化评估TMEM30A表达水平与缺血半暗带演进及神经功能的作用。本研究将提供该通路保护缺血半暗带的证据，为临床转化提供新思路。

The existence of retrievable penumbra is the basis for the successful reperfusion treatment after ischemic stroke. However, whether there is self-preservation or its potential application in clinics are still unclear. Recent research indicated that damaged neurons made their best to rescue themselves by various ways, which might be potential targets for future therapies. Our previous studies have found that TMEM30A is upregulated in the penumbra in focal ischemia models of both rhesus monkeys and rats. The role of TMEM30A in focal ischemia has not been reported despite recent findings indicating an important implication of TMEM30A/STAT in protection of other organs. We will confirm that TMEM30A/STAT pathway is increased in penumbra by both tissues from monkey and rats and cultured cells. Then, we will prove that TMEM30A/STAT pathway mediate apoptosis and stabilize cell membrane in vitro cell cultures by over-expressing or down-regulating target genes. We also associate TMEM30A/STAT pathway with penumbra progress and neural deficits in SHR rat, Tmem30a flox/flox -Thy1-Cre mice by MRI images, electrophysiology, and other methods. We will provide direct evidence on TMEM30A/STAT levels with penumbra evolution for further clinical applications.