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。 我们正在研究热休克蛋白70（HSP 70）在介导这种保护作用中的作用。 我们发现，热休克蛋白70抑制耳毒性毛细胞死亡。 我们最近的数据表明，HSP70在感觉毛细胞周围的胶质样支持细胞中表达。 支持细胞分泌HSP 70，并且这种分泌的HSP 70能够拯救毛细胞免于由耳毒性氨基糖苷类抗生素引起的死亡（May等2013 J.Clinical Investigation 123（8）：3577）。 这些数据表明，支持细胞是决定毛细胞在压力下最终存活或死亡的重要因素。 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 我们研究的一个重要目标是开发促进毛细胞存活和功能的临床疗法，以保护暴露于耳毒性药物、噪声创伤或其他毛细胞应激的人类的听力。 为了实现这一目标，我们正在研究在耳蜗中诱导热休克蛋白的方法。 为了将HSP诱导限制在内耳，我们最近研究了使用非创伤性声音暴露在耳蜗中诱导HSP的可行性。 我们的数据表明，非创伤性预处理声音可以导致HSP诱导小鼠耳蜗。 重要的是，这种预处理声音暴露抑制由顺铂或氨基糖苷类的全身施用引起的听力损失和毛细胞死亡（Roy，Ryals等人，2013 J. Clinical Investigation. 待印）。 提示声预处理对药物性听力损伤小鼠内耳有保护作用。

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 heat shock protein 70 (HSP70) in mediating this protective effect. We find that HSP70 inhibits ototoxic hair cell death. Our recent data indicate that HSP70 is expressed in glia-like supporting cells that surround sensory hair cells. Supporting cells secrete HSP70, and this secreted HSP70 is capable of rescuing hair cells from death caused by ototoxic aminoglycoside antibiotics (May et al 2013 J. Clinical Investigation 123(8):3577). These data indicate that supporting cells are important determinants of whether a hair cell under stress ultimately lives or dies. 2) Studies aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs An important goal of our studies is to develop clinical therapies that promote hair cell survival and function in order to preserve hearing in humans exposed to ototoxic drugs, noise trauma, or other hair cell stresses. Toward this goal we are examining methods of inducing HSPs in the cochlea. In order to restrict HSP induction to the inner ear, we have recently examined the feasibility of using non-traumatic sound exposure to induce HSPs in the cochlea. Our data indicate that non-traumatic preconditioning sound can result in HSP induction in the cochleas of mice. Importantly, this preconditioning sound exposure inhibits hearing loss and hair cell death caused by systemic administration of either cisplatin or aminoglycosides (Roy, Ryals et al. 2013 J. Clinical Investigation. In press). These data indicate that preconditioning sound can protect the inner ear against ototoxic drug-induced hearing loss in mice.