TSPO/VDAC1-ROS-线粒体自噬在糖尿病视网膜病变中的作用与机制研究

视网膜血管内皮细胞损伤是糖尿病视网膜病变（DR）发病的关键因素；ROS调控失衡是线粒体DNA氧化、内皮细胞损伤的重要原因；能否通过改变ROS水平延缓DR进程未知。研究表明线粒体跨膜复合物TSPO/VDAC1是调控ROS含量的关键，并因此改变线粒体自噬。我们的前期实验显示高糖下ROS及线粒体自噬水平增加，提示ROS-线粒体自噬可能参与DR进程；而TSPO/VDACI能否调节ROS含量影响线粒体自噬,对DR进行调控尚不清楚。为此，我们提出假设：TSPO/VDACI升高可以改变视网膜血管内皮细胞中ROS含量及线粒体自噬水平，通过ROS-线粒体自噬途径促进DR发展。本项目拟体内外实验检测TSPO/VDAC1-ROS-线粒体自噬在DR中的激活状态；靶向下调TSPO/VDAC1通过抑制ROS、改变线粒体自噬水平，以观察对DR的保护作用；从ROS-线粒体自噬角度探讨DR发病机制并为治疗靶点提供理论基础。

Retinal vascular endothelial cell damage is a key factor in the progression of diabetic retinopathy (DR). ROS control imbalance is the crucial cause of mitochondrial DNA oxidation and endothelial cell injury. Whether the DR process can be delayed by changing ROS levels is unknown. Studies have shown that mitochondrial transmembrane complex TSPO/VDAC1 plays a vital role in regulating ROS content and therefore changes the autophagy of mitochondria. Our previous experiments showed that ROS and mitochondrial autophagy levels increased in high sugar, suggesting that ROS- mitochondrial autophagy may be involved in DR process. It is not clear whether TSPO/VDACI could regulate ROS content to affect mitochondrial autophagy and thus, we hypothesized that the rise of TSPO/VDACI could change the ROS content and mitochondrial autophagy level in retinal vascular endothelial cells, and promote DR development through the ROS- mitochondrial autophagy pathway. This project tested the activation status of TSPO/VDAC1-ROS-mitochondrial autophagy pathway in the pathogenesis of DR in vivo and in vitro. TSPO/VDAC1 was down-regulated in order to inhibit ROS and change the autophagy level of mitochondria, and then observed its protective effect on DR process. We will provide a theoretical foundation to understand the pathogenesis and find new treatments of diabetic retinopathy from the perspective of ROS- mitochondrial autophagy.