药物性耳聋是儿童后天致聋因素之一。我们前期研究表明，新霉素等氨基糖苷类药物致聋存在窗口期，且窗口期内新霉素损伤可导致ATP受体亚型P2X7R表达增高。大量研究提示ATP释放可激活P2X7R，导致细胞膜大膜孔开放，使大分子物质进入细胞，造成细胞凋亡或死亡。因此我们推测P2X7R可能是介导新霉素进入毛细胞的关键离子通道。本项目拟从新霉素的耳毒性作用以及P2X7R的受体功能两方面入手，利用药物性耳聋及转基因小鼠的活体、离体多种研究模型，应用药理学方法调控受体功能或利用生物学技术调控转基因小鼠P2X7R受体表达，从新霉素耳毒性作用、P2X7R生理功能、P2X7R介导新霉素耳毒性的机制以及干预P2X7R功能调控新霉素耳毒性四个方面，研究新霉素在内耳毛细胞富集及并导致细胞凋亡的分子机制，揭示新霉素进入耳蜗毛细胞并诱导细胞凋亡的信号通路及免疫分子机制，将为药物性耳聋的防治提供理论依据和治疗靶点。

Drug ototoxicity is the main cause of hearing loss in children. It was reported that the inner ear hair cells were hypersusceptible to the aminoglycoside antibiotics (AmAb) due to the period of anatomia structure and function development in babyhood, which suggested that the ototoxicity was related to the microenvironment of the inner ear. Our recent studies explored that the postnatal day 8 to 14 was the hypersusceptible window period of mice, and furthermore, we found that the expression level of P2X7R was increased after neomycin injury..Previously studies indicated that release of ATP will trigger P2X7R activation, thus induce the membrane hole opening, which will help the big molecules intracellular immigration and induce cell apoptosis. Therefore, we presume that there should be some relationship between P2X7R and ototoxic-hearing loss, especially the mechanism of AmAn influx. We have planned to investigate both the metabolisms of AmAb ototoxicity to the inner ear and the function of P2X7R in the inner ear. We will use animal models of ototoxicity or P2X7R knockout transgenic mice with either biological ways or pharmacological methods to study the following subjects by the techniques such as immunohistochemistry, molecular biology, ABR test and so on; 1) Ototoxicity of neomycin; 2) Function of P2X7R in the inner ear; 3) Mechanisms of P2X7R involved in neomycin induced hair cell death; 4) regulation of P2X7R affected to the ototoxicity of neomycin. Our object is to reveal the relationship between P2X7R function and the key period of inner ear development in AmAb ototoxicity. Furthermore, we will explore the mechanisms of how neomycin entering the hair cell and to induce hair cell apoptosis, which while will support the evidence of the theory of the sensorineural hearing loss.