miR-375在视网膜血管内皮细胞增殖和血管新生中的作用及机制研究

Retinal neovascularization, one of the major causes of blindness in the world, is closely related with many ischemic retinal diseases, and there are no safe and effective therapies until now. It is reported that microRNAs(miRNAs) serve as key players in numerous physiological and pathological processes via negatively regulating the expression of target genes. Our previous study had revealed that expression of miR-375 was significantly down-regulated during retinal neovascularization. Moreover, miR-375 inhibited cell proliferation and weakened the abilities of cell migration and tube formation in retinal microvascular endothelial cells. Conversely, miR-375 inhibitor had the opposite effects. Meantime, miR-375 depressed the expression of ELAVL4 via directly binding to its 3′UTR. Inhibitory effects of miR-375 on cell proliferation and angiogenesis were attenuated by ELAVL4 overexpression. On the basis of these results, we will further explore the critical roles of miR-375/ELAVL4 in regulating retinal neovascularization and illustrate the corresponding molecular mechanism via combining utilization of endothelial cells, animal model and clinical samples. This study will provide an important theoretical basis and potential therapeutic target for the clinical treatment of proliferative retinopathy.

视网膜新生血管生成与许多缺血性视网膜疾病密切相关，是世界范围内主要的致盲病因之一，至今缺乏安全有效的治疗手段。研究证实microRNAs(miRNAs)可通过靶向负调控基因的表达参与影响许多生理和病理过程。我们前期研究发现在视网膜新生血管生成时miR-375的表达明显降低。细胞实验表明miR-375能够抑制视网膜微血管内皮细胞增殖并减弱内皮细胞迁移和小管形成的能力。反之，miR-375抑制物促进内皮细胞增殖和血管新生。同时，miR-375能直接结合到ELAVL4的3′UTR区并降低其表达。过表达ELAVL4能够减弱miR-375对视网膜血管内皮细胞增殖和血管新生的抑制作用。在此基础上，本课题拟进一步从细胞水平，动物模型和临床样本三个层次分别阐述miR-375/ELAVL4调控视网膜新生血管生成的作用及机制，从而为增殖性视网膜病变的临床治疗提供重要的理论依据和新的潜在治疗靶点。

视网膜新生血管生成与许多缺血性视网膜疾病密切相关，是世界范围内主要的致盲病因之一。深入研究其发病机制并探索潜在治疗靶点对临床应用极其重要和迫切。通过本项目的研究，我们阐述了miR-375在视网膜微血管内皮细胞增殖和血管新生中的作用并探究其调控机制，并研究了miR-29b及其调控的PDGF参与影响内皮细胞增殖的分子机制。我们发现在视网膜新生血管生成时表达明显降低的miR-375能够抑制视网膜微血管内皮细胞增殖并减弱内皮细胞迁移和小管形成的能力。机制研究发现miR-375能够靶向调节JAK2，并影响其下游Stat3的活化。而且，我们还研究了另一个microRNA（miR-29b）对视网膜微血管内皮细胞生长的调节作用。结果发现miR-29b-3p能够负向调节VEGF-A和PDGF-B的mRNA及蛋白质的表达，并显著地抑制血管内皮细胞的增殖和血管新生。而且，PDGF-B通过SHP-2/c-myc促进视网膜血管新生过程。总之，本项目的研究结果阐述了调控视网膜血管内皮细胞生长和血管新生的重要分子和作用机制，为眼内新生血管性疾病提供一些新的治疗策略和理论依据。