铜伴侣蛋白Atox1调控铜转运家族对顺铂耳蜗损害的保护作用及其机制研究

Cisplatin is one of the most common antitumor drugs clinically, but the high incidence of ototoxicity without definite intervention measures limit its application. Cisplatin and copper ion’s transport were via the same channel ,Copper transporter family( CTR1 ,ATP7A, ATP7B). Recent researches indicated that the loss of Atox1 will block the down-regulation of CTR1 induced by cisplatin and affected the ciapltin roll-out by ATP7A and ATP7B, change the amount of cisplatin in cells in finally. However, the specific mechanism of Atox1 which acted with cisplatin induced ototoxicity is unknown. In addition, Atox1 can promote the transcription of cyclinD1 and SOD3, and decrease the cells apoptosis.Our previous studies had shown that Atox1,CTR1,ATP7A and ATP7B richly expressed in inner ear, and the expression can be regulated by the intratympanic cisplatin and copper ion injection. So we put forward the hypothesis that Atox1 co copper transporter family regulate the transport of cisplatin in inner ear, mediate the transcription of cyclinD1 and SOD3 , decrease the apoptosis of cells and interfere with the occurrence of cochlear damage. The study try to investigate the protective mechanism of Atox1 on cisplatin induced cochlear damage from two aspects: cisplatin transport mechanism and cell apoptosis in cell,organ and animal levels. This study will provide new molecular targets and theoretical basis for the intervention of cisplatin induced cochlear damage.

顺铂是临床最常见的抗肿瘤药物之一，由于耳毒性发生率高且无有效的干预措施，限制了其应用。铜转运家族（Ctr1、ATP7A、ATP7B）是铜和顺铂共同的转运通道。有研究显示Atox1缺失能阻断顺铂诱导的Ctr1下调， 影响ATP7A、ATP7B对顺铂的转出，进而改变顺铂在细胞内的蓄积量。此外，Atox1可促进cyclinD1、SOD3转录，降低细胞凋亡。然而，Atox1在顺铂耳蜗损害中的作用不明。我们的前期研究显示Atox1与铜转运家族在大鼠内耳表达丰富，且铜转运家族受鼓室内顺铂、硫酸铜的调节。据此推测：Atox1通过调控铜转运家族影响顺铂在耳蜗的蓄积，同时介导cyclinD1和SOD3的转录，降低细胞凋亡来干扰顺铂耳蜗损害的发生。本项目拟在细胞、器官、动物水平从顺铂转运机制和细胞凋亡两方面探讨Atox1对顺铂耳蜗损害的保护机制。本研究的开展将为顺铂耳蜗损害的干预提供新的分子靶点和理论依据。

顺铂是临床最常见的抗肿瘤药物之一，由于耳毒性发生率高且无有效的干预措施，限制了其应用。铜转运家族（Ctr1、ATP7A、ATP7B）是铜和顺铂共同的转运通道。有研究显示Atox1缺失能阻断顺铂诱导的Ctr1下调， 影响ATP7A、ATP7B对顺铂的转出，进而改变顺铂在细胞内的蓄积量。此外，Atox1可促进cyclinD1、SOD3转录，降低细胞凋亡。然而，Atox1在顺铂耳蜗损害中的作用不明。我们的研究显示顺铂对耳蜗的损害通过降低 Atox1 和干扰 cyclin D1、SOD3 的表达，可能是氧化应激损害参与了顺铂耳蜗毒性性。毛细胞中atox1高表达能降低顺铂导致耳蜗的凋亡，动物实验显示Atox1的过表达载体注入耳蜗能够减缓顺铂造成的听力下降，对耳蜗具有保护作用。说明Atox1通过调控铜转运家族影响顺铂在耳蜗的蓄积，同时介导cyclinD1和SOD3的转录，降低细胞凋亡来干扰顺铂耳蜗损害的发生铂耳蜗损害的干预提供新的分子靶点和理论依据。