SDF-1/CXCR7信号轴调控内皮细胞谷氨酰胺代谢重编程在脉络膜新生血管形成中的作用及机制研究

脉络膜新生血管（CNV）最常见于年龄相关性黄斑变性（AMD）和病理性近视，是致盲的直接原因。尽管采用抗VEGF手段治疗CNV取得良好的短期效果，但需反复给药维持疗效。我们前期发现SDF-1/CXCR7 信号轴是一个非 VEGF/VEGFR2 通路依赖的，具有调节 CNV 形成的重要分子靶点，但具体机制不明。新近研究发现内皮细胞代谢途径的改变（代谢重编程）对新生血管的形成具有至关重要的作用。我们的预实验证实SDF-1/CXCR7轴能促进内皮细胞谷氨酰胺酶1表达和对谷氨酰胺摄入。本申请项目拟以脉络膜内皮细胞和CNV小鼠为对象，运用分子生物学手段探索SDF-1/CXCR7轴对内皮细胞谷氨酰胺代谢重编程调控的具体分子机制，并明确促细胞代谢正常化是否能有效抑制CNV的发生、发展。本项目成果将为研发基于 CXCR7 为分子靶点的 CNV 治疗新药，以及开展抗VEGF和抗内皮细胞代谢联合治疗提供新思路。

Choroidal neovascularization (CNV) is most common in age related macular degeneration (AMD) and pathologic myopia. Edema and hemorrhage from the hyperpermeable vessels of the CNV is the main cause of vision loss. Although the anti-vascular endothelial growth factor (anti-VEGF) therapy has become a standard treatment for CNV, the repeated treatment often causes the damage of the choriocapillaris and progression of macular atrophy. In our previous work, we found that the SDF-1/CXCR7 axis is a VEGF/VEGFR2 independent pathway, and is an important molecular target that regulates CNV formation in an experimental CNV model, but the exact mechanism remains unclear. Recently, the metabolic reprogramming of endothelial cells has been recognized as a driving force of angiogenesis. We previously verified that SDF-1/CXCR7 axis plays a key role in the regulation of glutaminase 1 (GLS1) expression and glutamate uptake in endothelial cells. In this research, we firstly confirm the relationship between CXCR7 expression and the reprogramming of glutamate metabolism in mouse primary choroidal endothelial cells (CECs) and human retinal microvascular endothelial cells (HRMECs). And then, by using the techniques of molecular biology, we will investigate the role of SDF-1/CXCR7-mediated glutamate metabolism reprogramming in the proliferation, survival, migration of endothelial cells and CNV formation. The results of this project will provide strong scientific evidences for developing of new drugs targeting CXCR7 to prevent blindness caused by CNV, as well as promoting a shift from a single anti-VEGF treatment to a model of anti-VEGF combined with anti-metabolic therapy for CNV.