应用嗅黏膜间充质干细胞外泌体干预高尔基体应激介导的铁死亡保护新生儿HIBD神经元的机制研究

神经元死亡是影响新生儿缺氧缺血性脑损伤（HIBD）预后的关键因素。间充质干细胞及其外泌体为减少神经元死亡提供了新的策略，但其机制尚不清楚。氧化应激是HIBD最重要机制之一，能介导神经元的铁死亡。本课题组率先提出高尔基体应激（GAS）的概念，概括了高尔基体与氧化应激相关过程，并证实GOLPH3是GAS标志性蛋白。最新研究发现GAS可促进铁死亡，调控神经元死亡；而目前高尔基体应激介导铁死亡在HIBD领域研究甚少。我们前期研究表明嗅黏膜间充质干细胞（OM-MSCs）通过抑制氧化应激，改善高尔基体功能紊乱，减少神经元死亡；且发现靶向GOLPH3的miR-486-5p在OM-MSCs-EXO中高表达。本项目拟探讨：OM-MSCs-EXO中 miRNA-486-5p通过靶向抑制GOLPH3参与调控高尔基应激介导的铁死亡,是减少HIBD神经元死亡的重要分子机制。本研究将为HIBD防治提供理论及实验基础。

Neuronal death is a key factor affecting the prognosis of neonatal hypoxic-ischemic brain damage (HIBD).Mesenchymal stem cells(MSCs) and MSCs-derived exosomes provided a new strategy to reduce neuronal death, but the potential mechanism remains unclear.Oxidative stress is one of the most important mechanisms of HIBD, which can mediate ferroptosis in neuronal death. Our research team was the first to put forward the concept of Golgi stress (GAS), summarized the process related to Golgi and oxidative stress, and confirmed that GOLPH3 is a landmark protein of GAS. Recent studies have found that GAS can promote ferroptosis and regulate neuronal death. However, there are few studies on ferroptosis mediated by GAS in HIBD. Our previously studies have shown that olfactory mucosal mesenchymal stem cells (OM-MSCs) can improve Golgi apparatus dysfunction and reduce neuronal death by inhibiting oxidative stress. Moreover, miR-486-5p targeting GOLPH3 was found to be highly expressed in OM-MSCS-EXO. This project aims to explore that miRNA-486-5p in OM-MSCS-Exo participates in the regulation of Golgi apparatus stress-mediated ferroptosis through the targeted inhibition of GOLPH3, and is an important molecular mechanism to reduce neuronal death in HIBD. This study will provide theoretical and experimental basis for the prevention and treatment of HIBD.