PINK1-Parkin-Optineurin通路调控高糖下RGC细胞自噬-利拉鲁肽改善DR的研究

Retinal ganglion cells (RGCs) are the only afferent neurons which can convey visual information to the visual cortex. They have long axons and abundant mitochondria. In the early stage of daibetic retinopathy(DR), the dysfunction of RGCs, the disorder of autophagy and the damage of axons had already occurred, all of these would ultimately leading to visual loss and even blindness. Glucagon-like peptide1(GLP-1) is an important and intelligent hypoglycemic drug, which is good for multiple organs in addition to hypoglycemic effects. The function of protecting neurons and regulating autophagy has been confirmed. Our group discovered the expression of GLP-1 receptor on RGCs for the first time in world wide, we also first proposed the theory that “early autophagy occured in axon is protective to RGCs, late autophagy occurred in soma induces cell death”. So we imagine whether GLP-1 analogue—liraglutide could protect RGCs by adjusting autophagy.Our study will explore the role of PINK1-Parkin-Optineurin pathway in regulating RGCs’ injury under high glucose condition focusing on mitochondria changes, and clarify the protective effect of liraglutide on RGCs by regulating mitophagy. This study will enrich the autophagy mechnism of DR, provide new insights for the early prevention and treatment of DR and come up with new ideas for the pleiotropic exploration of liraglutide.

视网膜神经节细胞（RGCs）是将视觉信息传递到视中枢的唯一传入神经元，其轴突长、线粒体丰富，在糖尿病视网膜病变（DR）早期即发生功能障碍、自噬紊乱、轴突受损，最终导致视野缺失甚至失明。胰高血糖素样肽-1(GLP-1)是里程碑式的智能降糖药物且具有降糖外的多脏器获益，保护神经，调控自噬已得到研究支持。本课题组在国际上首次发现RGCs表面GLP-1受体表达，曾率先提出“早期轴突自噬保护RGCs、晚期胞体自噬介导细胞死亡”这一崭新观点。故我们设想GLP-1类似物可否通过自噬途径保护RGCs？本研究拟从线粒体角度探究PINK1-Parkin-Optineurin自噬通路在高糖介导RGCs损伤中的作用；阐明利拉鲁肽干预线粒体自噬通路保护RGCs。本研究丰富了DR自噬机制，可为DR早期防治提供新途径，为利拉鲁肽降糖外的多效性探索开辟新思路。

视网膜神经节细胞（RGCs）是将视觉信息传递到视中枢的唯一传入神经元，其轴突长、线粒体丰富，在糖尿病视网膜病变（DR）早期即发生功能障碍、自噬紊乱、轴突受损，最终导致视野缺失甚至失明。胰高血糖素样肽-1(GLP-1)是里程碑式的智能降糖药物且具有降糖外的多脏器获益，保护神经，调控自噬已得到研究支持。本课题组在国际上首次发现RGCs表面GLP-1受体表达，曾率先提出“早期轴突自噬保护RGCs、晚期胞体自噬介导细胞死亡”这一崭新观点。故我们设想GLP-1类似物可否通过自噬途径保护RGCs？本研究拟从线粒体角度探究PINK1-Parkin-Optineurin自噬通路在高糖介导RGCs损伤中的作用；阐明利拉鲁肽干预线粒体自噬通路保护RGCs。结果表明，Optineurin调控自噬，参与高糖诱导的 RGCs 损害，利拉鲁肽可通过Optineurin调控RGCs自噬，保护RGCs，本研究丰富了DR自噬机制，可为DR早期防治提供新途径，为利拉鲁肽降糖外的多效性探索开辟新思路。