星形胶质细胞CXCL12/CXCR7信号通路在脑缺血损伤中的作用及机制研究

趋化因子CXCL12在缺血性脑损伤的组织修复及功能重建中发挥重要作用。近期研究表明CXCL12受体CXCR7在缺血性中风后皮质梗塞周围区域的表达显著增加，且主要定位在星形胶质细胞；而在梗塞核心的表达却明显降低，提示星形胶质细胞CXCL12-CXCR7信号通路在缺血性脑损伤中可能发挥着重要作用。但是星形胶质细胞CXCL12-CXCR7介导的信号通路在脑缺血中的作用及可能的分子机制尚不清楚。本项目拟构建星形胶质细胞靶向高表达及干涉CXCR7病毒，在缺氧细胞模型，局灶脑缺血再灌注大鼠及CXCR7基因敲除小鼠上，阐明星形胶质细胞CXCR7是CXCL12介导的信号分子通路的关键受体，并可能通过CXCL12-CXCR7信号通路参与脑缺血星形胶质细胞的功能调控；并进一步探讨星形胶质细胞CXCL12/CXCR7通路通过何种机制保护脑缺血神经元的功能。研究结果将为防治缺血性脑中风提供新的靶点和治疗策略。

Stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is a chemokine protein that ubiquitously expressed in many tissues and all cell types in the central nervous system. It has been reported that CXCL12 plays an important role in brain repair after ischemic stroke. Recent study has shown that ischemic stroke in human leads to an increase in the expression of CXCL12 and its receptor CXCR7, but not CXCR4, in the peri-infarct cerebral cortex. In addition, CXCR7 protein was predominantly expressed in astrocytes in the penumbra of ischemic brain in human, suggesting that CXCR7-mediated signaling pathway in astrocytes might play a key role in ischemic brain injury. However, the role of CXCR7 in astrocytes and its possible molecular mechanisms underlying its protective effects on neurons in cortex and CA1 after ischemia are not elucidated. Therefore, in this study, we will discuss the effects of astrocytic CXCL12-CXCR7-mediated signaling on brain injury in hypoxic cell model, focal cerebral ischemia reperfusion rats and astrocyte-targeting CXCR7 knockout mice. We will elucidate that CXCR7 might be the primary receptor of CXCL12 in astrocytes and CXCR7-mediated signaling might be involved in the functional regulation of astrocytes in ischemic stroke brain. In addition, we will further explore the underlying mechanisms for the regulation of CXCL12/CXCR7 signaling in astrocytes and its effect on the function of ischemic neurons after ischemia. This will provide new targets and therapeutic strategies for the prevention and treatment of ischemic stroke.