凋亡拮抗转录因子AATF介导远隔预处理诱导缺血脑保护的作用机制研究

It is demonstrated that remote preconditioning (RPC) can decrease the cerebral infarct size, moderate brain edema, and promote neurological function recovery; thus, it may have potent clinical translation potential. However, its regulatory mechanism need elucidated. On the other hand, it has been demonstrated that apoptosis antagonizing transcription factor (AATF) can resist DNA damage, reduce neuronal apoptosis, and regulate cell cycle. In our previous study, we found that AATF participated in neuronal protection after brain injury, and genome study showed that AATF related gene expression was up-regulated after RPC; additionally, its protein level in brain tissue was also increased after RPC. Therefore, we hypothesis that AATF plays an important role in RPC induced brain protection after cerebral ischemia. In order to verify our hypothesis, we will investigate the expression profile and cellular or sub-cellular locolization changes of AATF during RPC induced ischemic brain protection in the present project. And we will also investige the molecular mechanism involved in RPC induced AATF expression alteration. Meanwhile, regulatory role of AATF participating in RPC induced ischemic brain protection will be investigated. AATF overexpression and AATF-shRNA will be employed to investigate molecular mechanism of AATF induced neural protection via cellular ischemic preconditioning model. We hope to expose the biological mechanism that RPC induced ischemic brain protection and to provide evidence for its clinical translation,we also hope to find new pharmaceutic therapy target of endogenous brain protection through this project.

远隔预处理（RPC）能减少脑缺血后的梗死体积、减轻脑水肿、促进神经功能恢复，有重要的潜在临床转化价值，但其诱导脑保护的机制有待进一步阐明。凋亡拮抗转录因子（AATF）具有抗DNA损伤、抗凋亡、调节细胞周期的功能，课题组的前期研究发现AATF对神经损伤有保护作用、基因组学研究发现AATF相关的基因在RPC后表达上调、免疫印迹发现AATF在RPC组脑组织中表达增高，推测其很有可能是RPC诱导缺血脑保护的关键调控分子之一。本课题将进一步研究RPC诱导脑保护过程中AATF表达的动态变化、细胞/亚细胞定位改变，AATF表达增加的机理，AATF表达增加后通过何种途径介导RPC的脑保护作用，并通过AATF过表达和shRNA方法在预处理细胞模型上研究AATF的神经保护机制，以明确RPC 诱导缺血脑保护的关键调控分子、为RPC的临床转化提供依据，并为脑保护药物研究提供新的可能的干预靶点。

远隔预处理（RPC）能减少脑缺血后的梗死体积、减轻脑水肿、促进神经功能恢复，有重要的潜在临床转化价值，但其诱导脑保护的机制有待进一步阐明。凋亡拮抗转录因子（AATF）具有抗DNA损伤、抗凋亡、调节细胞周期的功能。本课题组进行了“凋亡拮抗转录因子AATF介导远隔预处理诱导缺血脑保护的作用机制研究”的研究，结果发现：(1) RPC诱导缺血脑保护过程中，大脑皮质AATF的mRNA和蛋白质的表达水平和定位均发生改变；(2) RPC诱导缺血脑保护过程中，通过Checkpoint激酶途径和/或泛素蛋白酶体途径调控了AATF的表达及定位改变；(3)证实RPC通过抗氧化应激、抗DNA损伤、抗神经元凋亡、调节神经元细胞周期等介导了缺血脑保护作用，且上述作用途径与AATF相关；(4) 明确了AATF是介导预处理神经保护的关键分子。.该项研究对RPC诱导脑保护的分子机制进行了更加深入的探讨,发现了AATF介导脑保护的作用机制,为进一步的深入研究和可能的药物靶点筛选提供了坚实的基础。