增生性玻璃体视网膜病变中Snail/DNMT1/HDAC1联合调控视网膜色素上皮-间充质细胞转换的机制研究

Proliferative vitreoretinopathy (PVR) is one of the major problems leading to blindness in patients with retinal detachments. An important event in the pathological process of PVR is retinal pigment epithelial (RPE) to mesenchymal transition (EMT). However, the mechanisms behind the RPE cells EMT is not yet entirely clear. Our previous studies have confirmed that Snail transcription factors, DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) were significantly up-regulated in transforming growth factor-β1 induced EMT in human RPE cells. Silencing Snail gene alone could reverse RPE-mesenchymal transition, but not completely canceled this process. Recent studies found that Snail united DNMT1 and HDAC1 to regulate the process of EMT in cancer progression. However, the role of Snail/ DNMT1/HDAC1 in RPE-mesenchymal transition is largely unknown. Therefore, we will investigate the role of Snail/ DNMT1/HDAC1 in RPE cells EMT and the mechanisms which may exist in this process from the cytology, histology and animal models. The completion of the project will further improve the PVR pathogenesis and lay the foundation for the prevention and treatment of PVR.

增生性玻璃体视网膜病变（PVR）是难治性致盲眼病，视网膜色素上皮（RPE）细胞发生上皮-间充质细胞转换（EMT）是PVR病理过程的主要事件，但EMT的调控机制尚未完全明确。我们前期研究证实，在TGF-β1诱导的RPE细胞EMT模型中Snail转录因子和表观遗传调节分子DNA甲基转移酶1（DNMT1）、组蛋白去乙酰化酶1（HDAC1）表达显著上调；单独沉默Snail基因可以逆转RPE-间充质细胞转换，但不能完全取消这一过程。研究表明，在一些癌症中Snail联合DNMT1和HDAC1共同调控EMT过程。然而，Snail/DNMT1/HDAC1在RPE-间充质细胞转换中的作用和机制仍不清楚。本项目将从细胞学、组织学和动物模型三方面调查Snail/DNMT1/HDAC1对RPE-间充质细胞转换的调控作用和机制。项目的完成将从表观遗传学角度进一步完善PVR发病机制，为临床预防和治疗PVR奠定基础。

增生性玻璃体视网膜病变(Proliferative vitreoretinopathy, PVR)是视网膜脱离的严重并发症，也是视网膜脱离手术失败最常见的原因。PVR以细胞性纤维膜组织在玻璃体和视网膜周围广泛增生为特征，最终因为纤维膜收缩对视网膜产生牵引导致视网膜结构和功能严重损伤，发生不可逆的视力丧失。研究发现，视网膜色素上皮细胞发生上皮-间充质细胞转换(Epithelial-Mesenchymal Transition, EMT)是PVR病理过程中成纤维样细胞的的重要来源。本项目主要研究视网膜色素上皮-间充质细胞转换的调控机制。研究内容聚焦于转录因子Snail过表达对视网膜色素上皮细胞的直接影响，同时通过转化生长因子β1诱导视网膜色素上皮细胞建立体外EMT模型，调查微小RNA 29b和长链非编码RNA MALAT1对视网膜色素上皮-间充质细胞转换的调控作用和机制，以及骨形态发生蛋白4对视网膜色素上皮-间充质细胞转换的抑制作用。此外，项目组还采集了PVR和孔源性视网膜脱离临床患者的玻璃体样本，完成了PVR临床代谢组学研究。项目的顺利完成，为进一步阐明PVR发病机制奠定了坚实理论基础，也为将来预防和治疗PVR提供了新的策略与方向。