Sestrin2激活Nrf2/HO-1通路促进脑缺血后血管再生的作用及机制研究

Cerebral microcirculation dysfunction is an initiating factor of series of pathophysiological during cerebral ischemia. Therefore, promoting angiogenesis in time and recovering blood perfusion in the ischemic regional cerebral effectively is particularly important. The literatures and our previous studies have shown that Nrf2 is an important factor in angiogenesis regulation, so clarifying its upstream regulatory factor and illustrating the regulatory mechanism is the scientific issues we will further explore and solve. In view of this, we put forward that Sestrin2 activates Nrf2 / HO-1 pathway probably by enhancing p62 induced degradation of Keap1, eventually promotes angiogenesis, reduces ischemic brain damage. This project will employ the brain microvascular endothelial cells, microglia and neuron co-culture model in vitro and photothrombotic cortical injury model in vivo which are closely to clinical. To explore the effects of Nrf2 on promoting angiogenesis and illuminate the activation of Sestrin2 on Nrf2 during cerebral ischemia, gene interference and over-expression and other molecular biology methods were apply and interfere in several aspects of the pathway. It will provide new directions and targets for prevention of cerebral ischemia.

脑微循环障碍是脑缺血一系列病理生理的始动因素，及时促进血管再生并有效的恢复缺血区域脑血流灌注尤为重要。文献报道及课题组前期研究均显示，Nrf2是重要的血管再生调控因子，明确其上游调控因子并阐明调控机制是我们即将深入探讨并解决的科学问题。因此，本项目提出：Sestrin2可能通过增强p62诱导的Keap1的降解，激活Nrf2/HO-1通路，从而促进血管再生，减轻缺血性脑损伤。本课题采用与临床接近的脑微血管内皮细胞、小胶质细胞和神经元细胞共培养体外模型和光化学栓塞法建立的脑缺血体内模型，应用基因干扰和过表达技术及其他分子生物学方法，从多个环节进行干预，探究Nrf2在脑缺血中的促血管再生作用，并阐明Sestrin2对Nrf2的激活作用，将为脑缺血的防治提供新的方向和靶标。

脑微循环障碍是脑缺血一系列病理生理的始动因素，及时促进血管再生并有效的恢复缺血区域脑血流灌注尤为重要。文献报道及课题组前期研究均显示，Nrf2是重要的血管再生调控因子，明确其上游调控因子并阐明调控机制是我们即将深入探讨并解决的科学问题。本项目提出：Sestrin2可能通过增强p62诱导的Keap1的降解，激活Nrf2/HO-1通路，从而促进血管再生，减轻缺血性脑损伤。本课题采用光化学栓塞法建立脑缺血体内模型，应用基因干扰和过表达技术、Western blot、免疫荧光、免疫共沉淀和PLA实验等技术，阐明，在脑缺血后，Nrf2具有一定的促血管生成作用；Sestrin2可以通过调节p62的表达进而影响Nrf2的入核，调控血管再生相关基因的表达，最终影响脑缺血后血管再生情况。该研究将为脑缺血的防治提供新的方向和靶标。