HucMSC外泌体miRNAs靶向抑制HIF-1α防治糖尿病视网膜病变的作用及机制

糖尿病视网膜病变（DR）患病率高是成人致盲的主要原因之一，早期防治是降低DR致盲的关键。我们前期研究发现，人脐带间充质干细胞源外泌体（hucMSC-Ex）能够延缓DR进程，减少炎症因子与促血管生成物质的释放，抑制HIF-1α表达及入核。通过外泌体miRNAs测序分析，我们筛选并初步验证出hucMSC-Ex中与HIF-1α相关的miRNAs分子。本研究拟采用CRISPR/Cas9基因编辑、电穿孔、细胞和动物模型干预等技术，旨在揭示hucMSC-Ex传递miRNAs抑制HIF-1α信号通路延缓DR的作用及机制，明确hucMSC-Ex作用的miRNAs动态调控表达谱，揭示hucMSC-Ex早期防治DR的关键miRNAs分子组合，评估具有靶向性的携载治疗性miRNAs工程化exosomes的疗效及安全性，为DR的防治提供新的方法，具有重要转化应用前景。

The high morbidity of diabetic retinopathy (DR) is one of the main causes of blindness in adults. Early prevention and treatment is the key to reduce the blindness. In our previous study, we found that human umbilical cord mesenchymal stem cell derived exosomes (hucMSC-Ex) could delay the progression of DR, inhibit the release of inflammatory factors and angiogenic substances, decrease HIF-1α expression and its nuclear translocation.We have screened and identified several miRNAs in hucMSC-Ex that are related to HIF-1α signaling pathway by miRNAs sequencing analysis.CRISPR/Cas9 gene editing, electroporation, cell and animal models will be used to identify the key miRNAs in hucMSC-Ex that are responsible for inhibiting HIF-1α signaling pathway, to clarify the dynamic changes of gene profile regulated by hucMSC-Ex miRNAs, to reveal the key miRNAs combination of hucMSC-Ex early prevention and treatment of DR and to evaluate the efficacy and safety of engineered targeted exosomes carrying therapeutic miRNAs. The results of this study will provide a new method for DR prevention and treatment. It has important application prospects.