Mechanisms of Sensory Hair Cell Survival and Death

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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.