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

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.

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。

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、HIF1α形成复合物，诱导HIF1α泛素化降解，减少VEGF分泌，抑制新生血管生成。本研究以RUNX3为靶点，以氧诱导视网膜病变（OIR）动物模型和低氧诱导的细胞模型为研究对象，通过体内外干预RUNX3的表达，研究RUNX3对PHD2-HIF1α-VEGF信号通路的调控及对视网膜新生血管形成的影响，并阐明RUNX3调控PHD2-HIF1α-VEGF信号通路抑制视网膜新生血管生成的机制。本研究主要取得了以下研究结果及科学意义：（1）RUNX3表达于增殖性糖尿病视网膜病变（PDR）患者的视网膜前纤维血管增殖膜，主要定位于血管内皮；（2）RUNX3在C57BL/6J乳鼠视网膜组织中表达，主要定位于血管内皮细胞，且在OIR造模后表达增加；（3）低氧刺激的人脐静脉内皮细胞（HUVEC）中RUNX3表达减少；（4）体外敲低HUVEC中的RUNX3，能抑制HUVEC增殖、迁移、内皮管腔形成能力；反之，体外过表达HUVEC中的RUNX3，能促进HUVEC的上述功能；（5）过表达小鼠视网膜组织中的RUNX3能抑制视网膜新生血管和无灌注区的形成。本研究结果丰富了目前对视网膜新生血管性疾病发病机制的理解，有望为RNV提供新的治疗靶点，具有重要的理论和临床意义。