SIRT1/NF-κB介导CEPO调控活性氧耐受促进创伤后脑微血管内皮细胞修复的实验研究

研究发现活性氧触发脑微血管内皮细胞损伤是导致颅脑创伤后血脑屏障损伤重要原因之一，诱导脑微血管内皮细胞对活性氧耐受（ROST)可显著减轻血脑屏障损伤。调控核受体活性,使促活性氧生成的相关传导因子染色质发生改变是诱导脑微血管内皮细胞对活性氧耐受的主要机制。而富集表达于神经系统的SIRT1又是调控核受体NF-kB 转录活性的关键性抑制因子，我们前期研究发现CEPO可激活SIRT1表达从而抑制下游分子NF-kB活性，促进创伤后脑微血管内皮细胞修复。.我们提出，如能证实CEPO是SIRT1关键调控因子，那促进SIRT1表达将从调控核受体NF-kB活性角度有效阻断活性氧对颅脑创伤微血管内皮细胞损害。本项目进一步研究CEPO—SIRT1—NF-κB信号通路及分子靶点对血脑屏障的保护机制，为创伤后血脑屏障保护新药开发提供理论依据。

One of the most important reasons for Blood brain barrier injury after traumatic brain injury(TBI) was the damage of cerebral microvascular endothelial cells . triggered by Reactive oxygen species(ROS) after TBI, and the damage of cerebral microvascular endothelial cells(CMEC) could be significantly alleviated after ROS tolerance (ROST) induced in CMECs. CMECs are injuryed by ROS through many sophisticated signal transduction pathways. Recent studies have demonstrated that changes on chromatin of specific ROS signal transduction proteins caused by nuclear receptors provided the major regulatory mechanisms for ROS induction. NF-kB was important nuclear receptors to activate CMECs caused by ROS, and receptor-interacting protein. Silent information regulation 1(SIRT1) mainly expressed in brain was one of the most important co-activator for NF-κB. The up regulation of SIRT1 promotes ROST in brain. Our previous study found that CEPO can activate SIRT1 expression to inhibit downstream molecular activity of NF-kB, promoting the repair of microvascular endothelial cells after traumatic brain injury..We put forward that if we can confirm that CEPO is a key regulatory factor to SIRT1, SIRT1 effectively blocked the damage of active oxygen on blood brain barrier. This project further study on the protection mechanism of CEPO -SIRT1- NF-κB signal transduction pathways and molecular targets on the blood-brain barrier, provides the theory for the development of new drugs to protect blood brain barrier after trauma.