RUNX3对PHD2-HIF1α-VEGF信号轴的调控在视网膜新生血管中的作用及机制研究

视网膜新生血管（RNV）的防治是目前眼科界的一大难题。研究发现PHD2-HIF1α-VEGF信号轴直接参与RNV的形成。RUNX3是一种新近发现的肿瘤抑制基因，其蛋白能与PHD2、HIF-1α形成复合物，诱导HIF-1α泛素化降解，减少VEGF分泌，抑制新生血管生成。我们预实验发现，缺氧状态下RUNX3在小鼠视网膜血管内皮细胞（mRMECs）中表达降低，对PHD2-HIF1α-VEGF信号轴调控作用减弱；而过表达RUNX3能够抑制低氧状态下mRMECs中VEGF分泌、增殖、迁移和血管发生。本研究将以RUNX3为靶点，以氧诱导视网膜病变动物模型和低氧诱导的mRMECs细胞模型为研究对象，通过体内外干预RUNX3的表达，从分子、细胞和整体水平研究RUNX3对PHD2-HIF1α-VEGF信号轴的调节机制及其对RNV生成的影响。该研究有望为RNV提供新的治疗靶点，具有重要的理论和临床意义。

Currently, the prevention and treatment of retinal neovascularization (RNV) is one of the most clinical challenges that the ophthalmologists face. It has been proved that the activation of PHD2-HIF1α-VEGF signal axis plays an important role in the development of RNV. RUNX3, a newly discovered tumor suppressor gene, directly bind with the activation domain of HIF-1α and PHD2, enhancing the interaction between HIF-1α and PHD2, which induce the degradation of HIF-1α in a ubiquitin dependent pathway, ultimatly inhibit the secretion of VEGF and angiogenesis in vitro and in vivo. Our previous studies have demonstrated that the decreasing of RUNX3 in mRMECs under hypoxic environment, weakened its role in regulating the PHD2-HIF1α-VEGF signal axis. In addition, overexpression of RUNX3 in mRMECs inhibited the secretion of VEGF, cellular proliferation, migration and angiogenesis induced by hypoxia. In this study, we focus on the role of RUNX3 in mRMECs and the mechanism by which it regulates the activation of PHD2-HIF1α-VEGF signal axis in the development of RNV by interfering the expression of RUNX3 in vivo and in vitro. This study is expected to provide a novel therapeutic target to control retinal vascular diseases, which has a profound theoretical and clinical significance.