顺铂所致肾损伤是常见的一类药物性肾毒性反应。TRAIL/DR5死亡受体通路在急性肾损伤中起重要调控作用。我们前期原创构建的可溶性DR5（sDR5）-Fc融合蛋白，可通过阻断TRAIL与DR5结合明显减轻顺铂处理小鼠肾损伤和减少肾小管上皮细胞的凋亡，上调热休克转录因子1（HSF1）表达；抑制HSF1可增加顺铂对小鼠肾损伤和促进P53磷酸化。由此，我们推测sDR5-Fc融合蛋白可能通过激活HSF1通路保护顺铂肾损伤。本项目拟采用DR5、HSF1、P53基因敲除小鼠及体外实验进一步研究：①sDR5-Fc融合蛋白对HSF1和热休克反应激活的影响；②分析其是否通过HSF1保护顺铂所致肾损伤；③探索sDR5-Fc融合蛋白是否通过调控HSF1-P53通路及内质网应激反应影响肾毒性损伤。该研究有助于揭示sDR5-Fc融合蛋白保护顺铂肾损伤的机制，并为治疗急性肾损伤提供候选创新药物。

Acute kidney injury (AKI) is the most common complication of cisplatin during tumor therapy. TRAIL-DR5 death signal pathway is an important mechanism of AKI. In our previous study, we find that the innovative soluble fusion protein DR5-Fc, which can block the interaction between TRAIL and DR5, obviously reduce cisplatin-induced AKI and the apoptosis of renal tubular epithelial cells and upregulate the expression of HSF1. In addition, we previously reported that HSF1 and the activated heat shock reaction have the ability in reducing cisplatin-induced AKI and P53 phosphorylation. Therefore, we hypothesized that sDR5-Fc fusion protein may protect cisplatin-induced renal injury by activating the Hsf1 pathway. This project intends to use DR5, HSF1, P53-knockout mice and in vitro experiment to further study: (1) the effect of sDR5-Fc fusion protein on the activation of HSF1 and heat shock reaction; (2) whether the protective effect of sDR5-Fc fusion protein on cisplatin-induced AKI is through HSF1; (3) whether the protective effect of sDR5-Fc fusion protein on cisplatin-induced AKI is through regulating HSF1-P53 pathway and endoplasmic reticulum stress. This study can help to reveal the mechanism of sDR5-Fc fusion protein protecting from cisplatin-induced acute renal injury and provide candidate innovative drugs for treating renal injury.