miR-200a/141调控HMGB1基因表达参与糖尿病视网膜病变发病机制的研究

Both our previous studies and overseas research teams have shown that the expression of miR-200a/141 was significantly decreased and the expression of HMGB1 increased in the diabetic retina. However the relationship between miR-200a/141 and HMGB1 and their effects on diabetic retinopathy remians unclear. Based on our pilot studies we hypothesize that miR-200a/141 may influence the expression of HMGB1 via regulating the expression of transcription factor RUNX1, and therefore promote the diabetic retinopathy. This study is the first attempt to approve the interaction and key binding sites between the seed sequence of miR-200/141 and RUNX1, between miR-200/141 and HMGB1 and between RUNX1 and HMGB1; and further definitude the regulatory action of miR-200a/141 on the expression and function of HMGB1, and their effects on the inflammatory reaction and biological behavior of diabetic retina. The study will not only help us reveal the pathogenesis and progress mechanism of diabetic retinopathy, but also provide new preventive and therapeutic approach for diabetic retinopathy.

我们和国外的研究证明，糖尿病视网膜组织中miR-200a/141表达降低，HMGB1表达增高，但二者之间的关系以及对糖尿病视网膜病变的影响和机制不清。通过系列前期研究提出工作假说，miR-200a/141可能直接影响HMGB1的表达；或者通过负性调控转录因子RUNX1的表达，上调HMGB1的表达影响糖尿病视网膜病变的发生发展。本项目拟首先验证miR-200/141通过"种子区"分别与HMGB1基因和RUNX1，以及RUNX1与HMGB1的直接作用和关键结合位点；进一步明确miR-200a/141对HMGB1基因表达和功能的调节作用，以及对视网膜组织炎症反应和生物学行为的影响。本项目不仅能深入揭示DR的发生发展机制，而且能为DR预防和治疗提供新靶点

本课题研究内容按预定进度安排如期进行， 取得了相应的结果。.本项目首先验证miR-200/141通过“种子区”分别与HMGB1基因和RUNX1，以及RUNX1与HMGB1的直接作用和关键结合位点；进一步明确miR-200a/141对HMGB1基因表达和功能的调节作用，miR-200a/141可以增加细胞生长活力和细胞增殖，通过抑制HMGB1的表达抑制细胞的炎症反应和凋亡水平，从而对高糖作用下的视网膜组织和视网膜内皮细胞具有保护作用；最后研究外源性给予miR-200/141模拟物以及siRNA- HMGB1单独和联合应用对糖尿病视网膜组织和REC细胞的作用效果。