肥胖症是现代社会常见的一种代谢性疾病，可引起睾丸内饱和脂肪酸水平升高及男性生育力降低。本项目前期研究发现，饱和脂肪酸可在睾丸支持细胞（Sertoli细胞）中异常堆积并损伤血睾屏障（BTB），但具体机制不清；进一步检测发现饱和脂肪酸可导致Sertoli细胞的RNA m6A水平降低及RNA m6A去甲基化酶ALKBH5升高，过表达ALKBH5可导致BTB相关基因下调表达，提示ALKBH5-m6A可能参与高脂所致BTB损伤过程。基于此，本项目拟：1.通过体内、体外实验，进一步阐明ALKBH5-m6A修饰在高脂所致BTB损伤过程中的作用；2.筛选其关键靶基因，进一步构建ALKBH5-m6A-下游靶基因的调节通路并阐明其具体机制，以期为临床上评估和治疗高脂因素所致男性生精障碍提供新的候选标志物及潜在靶点。

Obesity is a common metabolic disease in modern society, which can cause increasing of saturated fatty acids in the testes and declining of fertility in men. Preliminary studies in our group found that saturated fatty acids can abnormally accumulate in Sertoli cells and disrupt the blood-testis-barrier (BTB). However, the underlying mechanism is unclear. Further investigation revealed that saturated fatty acids decreased RNA m6A levels in Sertoli cells and elevated the expression RNA m6A demethylase ALKBH5. Overexpression of ALKBH5 can lead to down-regulation of BTB-related genes, suggesting that ALKBH5-m6A may participate in the process of BTB disruption caused by lipometabolic disturbance. Based on this, this project plans to: 1. further clarify the role of ALKBH5-m6A modification in the process of BTB disruption caused by lipid disturbance through in vivo and in vitro experiments; 2. screen the key target genes of ALKBH5 to further construct the ALKBH5-m6A-downstream target gene regulatory pathway and clarify its specific mechanism, hoping to provide new candidate markers and potential targets for clinical evaluation and treatment of male dyszoospermia caused by lipid disorders.