ROCK调控自噬参与青光眼术后瘢痕形成的作用及分子机制

The main reason for the failure of the filter passage after filtering surgery (GFS) is the scar. Previous studies have shown that the disorder of autophagy is closely related to the occurrence of scar formation, and regulation of autophagy plays an important role in the treatment of organ fibrosis disease such as in heart, liver, lung, kidney and other organs. The main function of Rho kinase (ROCK) is involved in the regulation of cell morphology, migration and movement. The preliminary results of the study show that the ROCK inhibitor K-115 could down regulate the activation and proliferation of Human Tenon 's Fibroblasts (HTFs) induced by TGF- beta1. The possible mechanism is to regulate the ability of autophagy of HTFs. However the mechanism of the interaction between them is worth further investigation. This project intends to establish GFS postoperative scar model both in vitro and in vivo, using cell biology, molecular biology, flow cytometry, transmission electron microscopy, experimental animal technology, to explore the molecular mechanisms of ROCK through regulating the function of autophagy impact scar formation. It may enrich and supplement our previous study, provide new ideas for the pathogenesis of filtering bleb scarring after GFS, and improve the long-term effect of GFS.

青光眼滤过性手术(GFS)后滤过道瘢痕化是导致手术失败的主要原因。研究表明成纤维细胞自噬失调与瘢痕化的发生密切相关，对自噬功能的调控在心、肝、肺、肾等器官纤维化疾病的治疗中显示出巨大潜力。Rho激酶(ROCK)的主要功能是调控细胞的形态、迁移与运动。课题组的预实验结果显示，ROCK抑制剂K-115可以下调TGF-β1诱导的人Tenon’s囊成纤维细胞(HTFs)的活化和增殖能力。其可能机制是调控了HTFs的自噬能力，但是它们之间相互调节的机制还值得进一步探讨。本项目拟建立离体及在体GFS术后瘢痕化模型，运用细胞生物学、分子生物学、流式细胞、透射电镜、实验动物等技术，探讨ROCK通过调控自噬功能影响瘢痕形成的分子机制。对前期研究进行丰富和补充；为ROCK调控瘢痕形成的作用机制开拓新的领域；为阐明GFS术后滤过道瘢痕化的发病机制提供新的思路；为提高GFS手术成功率提供新的手段。

青光眼滤过性手术(GFS)后滤过道瘢痕化是导致手术失败的主要原因。研究表明成纤维细.胞自噬失调与瘢痕化的发生密切相关，对自噬功能的调控在心、肝、肺、肾等器官纤维化疾病.的治疗中显示出巨大潜力。Rho激酶(ROCK)的主要功能是调控细胞的形态、迁移与运动。课题.组的预实验结果显示，ROCK抑制剂K-115可以下调TGF-β1诱导的人Tenon’s囊成纤维细胞(HTF.s)的活化和增殖能力。其可能机制是调控了HTFs的自噬能力，但是它们之间相互调节的机制还.值得进一步探讨。本项目建立了离体及在体GFS术后瘢痕化模型，分别证实了：诱导自噬是K115抗瘢痕的重要机制，对项目组前期已完成的研究结果进行了补充，为K115作用机制的研究开拓了新的领域，并提供了实验依据和理论依据，能进一步推动抗滤过道瘢痕药物的开发工作。由于K115作为抗青光眼滴眼液已经在一些国家上市，该药物抗瘢痕作用及机制的研究进一步拓宽了其临床应用范围。该课题的成功并推广，将有望推动新型安全有效的抗滤过道瘢痕药物的开发工作。