AMBRA1经旁效应调控自噬-铁死亡交互作用在高浓度草酸介导的肾结石形成中的机制研究

泌尿系结石是泌尿外科最常见的疾病之一，且患病率逐年增高，迫切需要对其病因机制进行深入研究。由预实验得知，经高浓度草酸处理后的HK-2细胞可分泌高表达AMBRA1基因的外泌体，其可与Beclin1结合促进自噬小体形成，诱导自噬发生，以往研究证明自噬在肾结石的发生发展中发挥重要作用，但其下游分子调控机制尚不明了。有研究表明，Beclin1不仅为自噬调控因子，亦可与胱氨酸/谷氨酸转运体亚基（XCT）结合，促进铁死亡发生。据前期研究提示铁死亡在尿石症形成过程中发挥重要作用，由此我们推测，外泌体来源AMBRA1可借由AMBRA1-Beclin1-XCT信号轴触发自噬-铁死亡交互作用诱发细胞损伤，促进结石形成。本项目拟采用现代分子生物学及生物信息学研究技术，对AMBRA1、自噬及铁死亡水平进行调控，从而阐明由外泌体触发的自噬-铁死亡交互作用的效应机制，为泌尿系结石的防治及精准治疗提供新的策略及方向。

Kidney stone is one of the most common diseases in urology, and the prevalence rate is increasing year by year. In-depth research on its etiological mechanism is urgently needed. It is known from preliminary experiments that HK-2 cells treated with high concentration of oxalate can secrete exosomes with high expression of AMBRA1 gene, which can be combined with Beclin1 to promote the formation of autophagosomes and induce the occurrence of autophagy. It plays an important role in the occurrence and development of kidney stones, but its downstream molecular regulatory mechanism is still unclear. Some studies have shown that Beclin1 is not only a regulator of autophagy, but also can be combined with cystine / glutamate transporter subunit (XCT) to promote ferroptosis. According to previous studies, ferroptosis plays an important role in the formation of urolithiasis. From this, we speculated that AMBRA1 derived from exosomes can trigger autophagy-ferroptosis interaction through the AMBRA1-Beclin1-XCT signaling pathway to induce cell damage and promote stone formation. This project intends to use modern molecular biology and bioinformatics research technology to regulate the levels of AMBRA1, autophagy and ferroptosis, so as to elucidate the effect mechanism of autophagy- ferroptosis interaction triggered by exosomes, and provide new strategies and directions for the prevention and treatment of urinary tract stones and precise treatment.