经新型纳米胶束温敏水凝胶递释的microRNA-26a抑制青光眼滤过泡瘢痕形成的作用及机制研究

The postoperative scarring remains a critical determinant of the long-term surgical outcome and intraocular pressure after glaucoma filtration surgery. There is a large unmet need to develop more effective, more specific, and safer therapies to prevent postoperative scarring. In our previous study, we have found miRNA-26a could inhibit the proliferation and migration ability of Tenon’s fibroblasts in the presence of TGF-ß2. In the present study, we aim to offer novel therapeutic intervention with miRNA-26a for the postoperative scarring of glaucoma filtration surgery. Here, we developed a chitosan-based nanomicelle carrier to deliver miRNA-26a into fibroblasts. We would evaluate the characteristics of amphiphilic nanomicelle, and further investigate its antiscarring effect and safety in vitro cell culture; then we would develop thermo-sensitive hydrogel based on Pluronic mixture for the sustained release in situ, and evaluate its antiscarring effect and safety in vivo animal study. Finally, we will systematically screen the scarring-related targets and reveal the down-stream signal pathways to fully elucidate the underlying mechanism.

滤过泡过度瘢痕化愈合是导致青光眼滤过术失败的主要原因之一，临床中尚缺乏安全、特异、有效的治疗方法，亟待进一步研究解决。我们前期研究结果表明miRNA-26a对TGF-β2介导的Tenon’s囊成纤维细胞（HTF）增殖和迁移具有显著的抑制作用。本项目拟从特异性对抗滤过泡瘢痕化的病理机制出发，针对miRNA-26a，探寻具有临床应用前景的抗滤过泡过度瘢痕化治疗新方法。项目组前期已初步构建负载miRNA-26a的两亲性壳聚糖基纳米胶束，提示该纳米载体可高效递释miRNA-26a进入HTF细胞内。基于此，项目组将进一步鉴定其性质表征，明确其抗瘢痕化作用的细胞学基础；研制组合式配方泊洛沙姆温敏水凝胶以达到术中注射、术后原位缓释的目的，并通过动物模型实验评价其抗瘢痕化作用的有效性和安全性；最后研究经纳米胶束递释的miRNA-26a所直接调控的滤过泡瘢痕化相关靶基因和下游信号通路，全面揭示其分子机制。

滤过泡过度瘢痕化愈合是导致青光眼滤过术失败的主要原因之一，临床中尚缺乏安全、特异、有效的治疗方法，亟待进一步研究解决。本项目成功构建载miR-26a两亲性壳聚糖基纳米胶束以递释miR-26a进入结膜囊成纤维细胞内，并研制泊洛沙姆温敏水凝胶给药系统以达到术中注射给药、术后原位储药缓释的目的。项目通过细胞和动物模型实验验证载miR-26a壳聚糖基纳米胶束泊洛沙姆温敏水凝胶抗青光眼滤过泡瘢痕化作用的有效性和安全性，并采用基因芯片测序技术，结合瘢痕化相关信号通路基因集富集分析、差异表达基因趋势分析以及生物信息学预测工具筛选靶基因并初步验证。本项目研究成果将为基于miR-26a的新型抗青光眼滤过泡过度瘢痕化治疗药物的研发提供一定的科学依据。