Exosome传输的circ2098信号在NLRP3介导视网膜氧化损伤中的作用及机制研究

老年性黄斑变性（AMD）是导致我国老年人口视力损伤的重要疾病。炎性小体NLRP3介导的氧化损伤参与其病理过程。我们前期发现视网膜色素上皮细胞（RPE）损伤为中心事件、小胶质细胞过度活化并通过NLRP3途径加剧视网膜损伤。外泌体是细胞间的信号传导媒介，我们预实验发现RPE损伤后分泌的外泌体可刺激正常细胞产生NLRP3；外泌体测序和鉴定进一步提示环状RNA（circ2098）表达上调；circ2098可通过“海绵”机制阻断miR-22-3p对NLRP3的抑制。我们据此提出假说：源于损伤RPE的外泌体传输circ2098，促进NLRP3介导的视网膜氧化损伤。围绕该假说，本研究拟在前期工作基础上，通过细胞水平和动物模型探讨外泌体传输circ2098的角色，进一步研究circ2098阻断miR-22-3p在NLRP3介导的视网膜氧化损伤中的作用，为探索AMD的发病机制和干预策略提供新思路。

Age-related macular degeneration (AMD) is one of the leading courses of vision loss in elderly population. NLRP3 mediated oxidative damage involves in this pathological process. Our previous work suggests that the impairment of retinal pigment epithelium (RPE) is the key to retinal oxidative damage, and activation of microglia exacerbates retinal degeneration via NLRP3 pathway. Exosome has been identified as a small endogenous nanocarrier involved in intercellular signals transduction. We have previously found that exosomes secreted from oxidatively damaged RPE could increase NLRP3 inflammasome in normal RPEs and microglia. High-throughput sequencing of exosomal RNAs further identified circ2098 as a significantly up-regulated circular RNA upon oxidative stress. Bioinformatic analysis indicated that circ2098 could be the sponge of miR-22-3p, alleviating the inhibited effect of miR-22-3p on NLRP3. Taken together we assume that exosome is a crucial vehicle for intercellular transportation of circ2098, which activates NLRP3 by sponging miR-22-3p. This proposal is to explicate the role of exosome in circ2098 transportation, and to explore the regulatory effect of circ2098 in NLRP3 activation in retinal degeneration. This work could reveal the role of exosomal circ2098 in AMD pathogenesis and provide novel targets for future treatment of AMD.