小胶质细胞来源的Exosome携带lncRNA MIAT介导视网膜炎性损伤的作用及机制研究

Age-related macular degeneration (AMD) is one of the leading courses of vision loss. The non-infectious inflammation and death of retinal pigment epithelia (RPE) cells involve in its pathological process. Exosome, as extracellular vesicle, is emerging as a key mediator of intercellular communication and inflammation. Our previous work suggests that activation of microglia exacerbates retinal degeneration. Exosomes derived from microglia are enriched of MIAT which has the potential to activate NLRP3 inflammasome in normal RPE cells. In addition, miR-22-3p was identified as the suppresser of NLRP3 mRNA, whereas there is also binding site for miR-22-3p in MIAT gene. Taken together we assume that exosome is a crucial vehicle for intercellular transportation of MIAT, which activates NLRP3 by sponging miR-22-3p. This proposal is to explore the role of exosome in MIAT transportation, the MIAT/miR-22-3p/NLRP3 pathway, and the therapeutic potential of exosomes enriched of miR-22-3p in retinal inflammation. This work would shed light the AMD pathogenesis and provide novel targets for treatment of AMD.

老年性黄斑变性（AMD）是重要的致盲性眼病，炎症可加剧其病理损伤，表现为视网膜色素上皮细胞（RPE）的变性和死亡。外泌体作为细胞间信号传导媒介，在介导炎症应答中发挥重要作用。我们前期发现小胶质细胞的活化加剧视网膜炎性损伤，其分泌的外泌体通过测序提示Lnc MIAT上调，并能够激活RPE内NLRP3炎性小体；而miR-22-3p可抑制RPE内NLRP3表达；miR-22-3p与MIAT也有结合位点。我们据此提出假说：活化的小胶质细胞分泌的外泌体携带MIAT，竞争性抑制miR-22-3p，进而激活RPE胞内NLRP3，介导视网膜炎性损伤。围绕该假说，本项目拟在前期工作基础上，通过细胞水平和动物模型研究，明确外泌体传输MIAT的角色，验证MIAT/miR-22-3p/NLRP3信号通路，并探讨装载miR-22-3p的外泌体对视网膜炎性损伤的保护作用，为探索AMD的发病机制和干预靶点提供思路。

老年性黄斑变性（AMD）是重要的致盲性眼病，炎症可加剧其病理损伤，表现为视网膜色素上皮细胞（RPE）的变性和死亡。外泌体作为细胞间信号传导媒介，在介导炎症应答中发挥重要作用。在国自然青年基金项目（81900875）的支持下，我们证明了小胶质细胞是增殖性糖尿病视网膜病变纤维血管膜上的主要细胞，其重要的亚型M（1）具有促纤维、成纤维效应；验证了活化的小胶质细胞分泌的外泌体可以上调视网膜色素上皮细胞内的NLRP3炎性小体，进而介导视网膜炎性损伤的理论；拓展了M2类型的小胶质细胞分泌的外泌体可以促进视网膜血管朝向正常化新生的研究；探讨了müller细胞来源的外泌体通过miR-9-3p/S1P1通路促进视网膜新生血管的机制。以上成果为探索外泌体在眼底病中的的发病机制和干预靶点提供思路。