TRPM2/ATM信号通路介导的DNA损伤应答在顺铂致急性肾损伤中的作用研究

顺铂引起急性肾损伤(AKI)是临床常见危急重症。瞬时受体电位M2(TRPM2)缺失减轻小鼠缺血再灌注引起的AKI。本课题组前期工作发现：顺铂诱导的TRPM2基因敲除小鼠AKI程度较野生型小鼠严重、磷酸化ATM和Chk2水平下调；顺铂处理下HEK-293细胞核内TRPM2信号增强，提示TRPM2在顺铂致AKI中有不同于缺血再灌注损伤的作用，但具体机制不明。结合文献报道，顺铂导致DNA损伤可激活DNA损伤应答(DDR)，TRPM2通过介导ATM调控肿瘤细胞DDR，我们提出假说：顺铂导致的DNA损伤刺激TRPM2入核，触发ATM启动DDR，进行DNA损伤修复以减轻AKI。本项目拟通过基因敲除小鼠、腺相关病毒过表达等技术从分子、细胞和动物水平多层次明确TRPM2在顺铂致AKI中的作用，探讨TRPM2触发ATM的机制，揭示TRPM2调控DDR抑制顺铂致AKI的机理，为防治顺铂相关性AKI提供新思路。

Cisplatin-induced acute kidney injury (AKI) is a clinical common emergency severe disease. Transient receptor potential melastatin 2 (TRPM2) deletion alleviated the injury induced by ischemia-reperfusion in mice. Our previous study found that the injury in TRPM2-knockout mice was more serious than that in wild-type mice after treated by cisplatin, and the level of phosphorylated ATM and checkpoint kinase 2 (Chk2) protein in TRPM2-knockout mice was significantly lower than that in wild-type mice; meanwhile, the signal of TRPM2 was enhanced in HEK-293 nucleus after treated by cisplatin, overall, these results suggested that TRPM2 played a different role in cisplatin-induced AKI, but the mechanism is still unclear. Previous studies had indicated that DNA damage induced by cisplatin activates DNA damage response (DDR), and TRPM2 triggers ATM kinase to initiate DDR in tumor cells. So we propose a hypothesis: DNA damage induced by cisplatin stimulates TRPM2 to enter the nucleus and trigger ATM kinase to initiate DDR, in order to repair DNA damage and alleviate AKI. This project intends to reveal the role of TRPM2 in cisplatin-induced AKI and the molecular mechanism of TRPM2 triggers ATM regulating DDR in cisplatin-induced AKI at molecular, cellular and mice levels, by using of gene knockout mice, adeno-associated virus overexpression technology and so on. It will provide new way for exploring new prevention and treatment of cisplatin-induced AKI.