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。 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 我们最近发现，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。 2011年1月，我以终身研究员的身份来到NIH。 2011年，我花了很大一部分时间为实验室配备人员和订购设备。

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. 2) Studies aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs We have recently shown 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. I arrived at NIH as a Tenure-track Investigator in January 2011. I have spent a significant portion of 2011 staffing the laboratory and ordering equipment.