Mechanisms of Sensory Hair Cell Survival and Death

1)旨在了解热休克蛋白保护作用的分子机制的研究 我们的研究表明，温和的热应激诱导胞果的保护状态。 我们正在研究两种特异性热休克蛋白（HSP 70和HSP 32）作为这种保护作用的介质的作用。 我们发现这些分子中的每一种都抑制耳毒性毛细胞死亡。 此外，这两种分子都抑制氨基糖苷类药物处理的毛细胞中促凋亡c-Jun N-末端激酶（JNK）的活化。 我们目前正在研究内耳中哪些细胞类型通过上调HSP 70和HSP 32对压力做出反应。我们最近的研究表明，HSP 70和HSP 32可能在感觉毛细胞以外的细胞类型中被诱导。 2)研究旨在将我们的发现转化为临床治疗，以预防暴露于耳毒性药物引起的听力损失 我们最近发表了我们的研究结果，即一种名为雷公藤红素的HSP诱导剂可以抑制氨基糖苷类药物诱导的小鼠毛细胞死亡和听力损失。 我们还发现雷公藤红素保护作用的机制是通过诱导HSP 32。 我们目前正在研究在内耳中诱导HSP的其他方法，目的是开发一种联合治疗，以保护接受耳毒性药物的人类患者的听力。为了实现这一目标，我们最近开发了一种顺铂诱导的小鼠听力损失模型系统。 这种新的模型系统将使我们能够在体内进行保护性治疗的临床前研究。

1) Studies aimed at understanding the molecular mechanisms underlying the protective effects of HSPs Our studies indicate that a mild heat stress induces a protective state in utricles. We are investigating the roles of two specific HSPs (HSP70 and HSP32) as mediators of this protective effect. We find that each of these molecules inhibits ototoxic hair cell death. In addition, both of these molecules inhibit activation of pro-apoptotic c-Jun N-terminal kinase (JNK) in hair cells treated with aminoglycosides. We are currently examining which cell types in the inner ear respond to stress by upregulating HSP70 and HSP32. Our recent studies indicate that HSP70 and HSP32 may be induced in cell types other than sensory hair cells. 2) Studies aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs We have recently published our findings that a pharmacological HSP inducer called celastrol inhibits aminoglycoside-induced hair cell death and hearing loss in mice. We also showed that the mechanism underlying celastrols protective effect is via induction of HSP32. We are currently examining additional methods of inducing HSPs in the inner ear with the goal of developing a co-therapy that will protect the hearing of human patients receiving ototoxic drugs. In order to accomplish this, we have recently developed a model system of cisplatin-induced hearing loss in mice. This new model system will allow us to perform pre-clinical studies of protective therapies in vivo.