脐带间充质干细胞来源外泌体调控靶细胞应答抑制YAP活性延缓糖尿病肾病的作用及机制研究

课题组前期研究表明脐带间充质干细胞来源外泌体（hucMSC-Ex）对肾、皮肤、肝、心肌等组织损伤模型有良好的修复效果，显示在再生医学领域的广阔应用前景。糖尿病肾病（DKD）的防控是健康中国2030规划的重要内容，预实验结果发现hucMSC-Ex能够显著地降低糖尿病肾病（DKD）模型鼠的血糖并延缓其病程，可能是通过磷酸化依赖途径促进了YAP蛋白的胞质内滞留和泛素化降解，进而抑制其生物学活性，但确切的分子机制亟待阐明。因此，本研究将采用CRISPR/cas9基因编辑、单细胞测序、LC-MS/MS、免疫共沉淀等技术，结合YAP特定磷酸化位点突变小鼠模型，深入探讨hucMSC-Ex延缓DKD的作用及机制，明确hucMSC-Ex调控YAP磷酸化的关键分子及相关信号通路，揭示hucMSC-Ex作用的肾组织靶细胞及靶细胞对外泌体的应答，为糖尿病肾病的预防和治疗提供新策略。

Our previous studies have proved that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) have shown promising results in renal, skin, liver and myocardial injury model, can be exploited as powerful tool in regenerative medicine. The prevention and therpty of diabetic kidney diseases(DKD) is an important part of the health China 2030 program. We have found that hucMSC-Ex can significantly decrease the level of blood glucose and delay the occurrence in DKD models.The function of hucMSC-Ex may be related to promote YAP cytoplasmic retention and ubiquitination degradation. However, the role and mechanism of hucMSC-Ex in DKD remains unclear. Therefore, this study will use CRISPR/cas9 gene editing, single cell sequencing, LC-MS/MS, co-immunoprecipitation and other cellular and molecular biology techniques, combined with YAP specific phosphorylation site gene mutation mouse model, investigate the mechanism of hucMSC-Ex on the prevention and treatment of diabetic kidney diseases. We will identify the key molecules and associated signaling pathways for regulating YAP phosphorylation by hucMSC-Ex, elucidate the response pathway of the renal tissue target cells and provide a new strategy to prevent and treat DKD.