目前已知炎症损伤是导致脑缺血再灌注损伤的重要病理环节，并已明确部分炎症介质调控通路，但仍不能完全解释脑缺血再灌注损伤中炎症损伤的详细机制。前期我们已经发表文章报道：circRNA-015947表达上调参与脑缺血再灌注损伤的发生。近期预实验结果显示，circRNA-015947可吸附炎症相关miRNA（miR-188-3p）。我们推测，在脑缺血再灌注损伤的过程中，存在一种circRNA-miRNA-mRNA的调控网络机制，从而促进脑缺血再灌注损伤中局部过度的炎症反应。本项目拟在前期研究基础上，采用海马神经元氧糖剥离再灌注损伤模型，通过基因过表达和沉默技术明确circRNA-015947在脑缺血再灌注炎症损伤中的作用。同时，深入解析其下游效应途径及靶点，为脑缺血再灌注损伤的防治提供新的分子靶点。

Inflammatory damage plays an important role in cerebral ischemia/reperfusion injury (IRI). Nowadays, many researches had focused on the regulation pathways of inflammation response in cerebral IRI, but still can not fully explain the mechanism of inflammatory response-mediated cerebral IRI. Our previous studies have demonstrated that the overlapping expression of circRNA-015947 might be involved in the process of cerebral IRI. Through the gene transfection technology and bioinformatics analysis, we also found that up-regulated expression of circRNA-015947 could interact with miR-188-3p and thereby enhance inflammatory response. Therefore, we speculate that circRNA-miRNA-mRNA regulation network is the essential pathological process of local excessive inflammation response in cerebral IRI. In the proposed application, we will use different approaches such as gene over-expression and gene silencing assay to understand how circRNA-015947 can affect the inflammatory response-mediated cerebral IRI. What is more, we will focus on disclosing the molecular mechanisms regulated by circRNA-015947 in circRNA-miRNA-mRNA regulation pathway. The results generated from the propose study lays a novel foundation for the role of circRNA-015947 as s regulator of inflammatory response and offer new avenues for therapeutic intervention against inflammatory response-mediated cerebral IRI.

缺血性卒中是神经系统的常见病及多发病，具有发病率高、死亡率高、残疾率高和复发率高等特点，给社会和家庭带来沉重负担。目前，临床上缺血性卒中的主要治疗措施是釆用组织型纤溶酶原激活物（tissue type plasminogen activator, t-PA）溶栓以恢复脑组织血流。但是，由于受缺血后6小时治疗时间窗的限制，仅有3-5%的患者适用。因而，寻求新的治疗措施极为迫切。 我们前期研究发现，在海马神经元细胞缺血再灌注损伤模型中circRNA-015947表达上调，但是后继生物信息学分析没有发现其下游存在与神经功能相关的靶基因。因此，我们选择与凋亡通路相关的circRNA-0002207做进一步的研究。通过谷氨酸诱导海马神经元细胞缺血损伤模型，研究发现circRNA-0002207表达上调参与了细胞损伤。在细胞活性检测中发现，沉默circRNA-0002207可逆转谷氨酸对海马神经元细胞的损伤作用，从而对神经元细胞起保护作用。进一步的检测发现沉默circRNA-0002207可抑制Caspase3蛋白的活化，从而抑制细胞凋亡，这可能是沉默circRNA-0002207对海马神经元细胞起保护作用的重要机制之一。 本研究证实circRNA-0002207在脑缺血损伤中起重要作用；揭示circRNA-0002207通过凋亡相关通路参与脑缺血损伤的分子机制，为解释脑缺血损伤的发病机制及其早期干预治疗提供新的理论依据。