Mechanisms of Sensory Hair Cell Death and Survival

描述（由申请人提供）：人类听力和平衡障碍通常是由于感觉毛细胞的死亡。这些细胞对噪声暴露、衰老和一些治疗药物（包括氨基糖苷类抗生素和顺铂）诱导的死亡敏感。这项研究计划的目标是了解毛细胞死亡和存活的分子机制。详细了解这些细胞机制对于设计旨在预防听力损失的疗法至关重要。热休克蛋白（Hsps）的诱导是一种普遍存在的高度保守的反应，在许多系统中可以显着抑制细胞凋亡。我们的数据表明，热休克蛋白70的诱导是一个关键的压力反应，在内耳，可以促进毛细胞暴露于主要的压力源的生存。Hsp 70对毛细胞死亡的保护作用的机制尚不清楚。我们的数据表明，热休克蛋白70的诱导主要发生在支持细胞与毛细胞的诱导很少，这表明支持细胞介导的热休克蛋白70对毛细胞死亡的保护作用。我们推测，热休克蛋白70分泌的支持细胞和内化的毛细胞，在那里它作为一个分子伴侣和凋亡信号的抑制剂。四组实验来验证这一假设：目的1是确定是否支持细胞Hsp 70是必要的和足够的Hsp 70对毛细胞死亡的保护作用。目的2：探讨热休克蛋白70的抗凋亡和分子伴侣活性在其抗毛细胞死亡保护作用中的作用。目的3：研究支持细胞Hsp 70的保护作用是否通过支持细胞分泌Hsp 70和毛细胞内化介导。目的4是确定介导毛细胞-支持细胞通讯的细胞间信号对应激的反应。从临床的角度来看，清楚地了解毛细胞死亡和生存的机制，以响应耳毒性药物将是至关重要的合理设计的共同治疗，旨在防止听力损失和平衡障碍造成的。我们的数据表明，热休克蛋白70是保护毛细胞死亡引起的氨基糖苷类和顺铂，因此，它代表了一个潜在的治疗目标，这两类耳毒性药物。从基础科学的角度来看，该项目解决了在压力下毛细胞中促生存和促死亡信号之间相互作用的细胞生物学。此外，该研究计划还研究了毛细胞和支持细胞之间相互作用的基本性质。 公共卫生相关性：该项目的重点是每年至少有50万美国人因暴露于治疗药物而导致的听力损失。该项目旨在研究暴露于这些药物的内耳感觉细胞死亡和存活的机制。了解这些机制将指导旨在预防耳毒性药物引起的听力损失的治疗方法的发展。

DESCRIPTION (provided by applicant): Human hearing and balance impairments are often due to death of sensory hair cells. These cells are sensitive to death induced by noise exposure, aging, and some therapeutic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. The goal of this research program is to understand the molecular mechanisms underlying hair cell death and survival. Understanding these cellular mechanisms in detail will be critical for the design of therapies aimed at preventing hearing loss. Induction of heat shock proteins (Hsps) in response to cellular stress is a ubiquitous and highly-conserved response that can significantly inhibit apoptosis in many systems. Our data indicate that Hsp70 induction is a critical stress response in the inner ear that can promote survival of hair cells exposed to major stressors. The mechanism(s) underlying the protective effect of Hsp70 against hair cell death are not known. Our data indicate that Hsp70 induction occurs primarily in supporting cells with little induction in hair cells, suggesting that supporting cells mediate the protective effect of Hsp70 against hair cell death. We hypothesize that Hsp70 is secreted by supporting cells and internalized by hair cells, where it acts as both a molecular chaperone and an inhibitor of apoptotic signaling. Four groups of experiments are proposed to test this hypothesis: Aim 1 is to determine if supporting cell Hsp70 is necessary and sufficient for the protective effect of Hsp70 against hair cell death. Aim 2 is to determine the roles of the anti-apoptotic and chaperone activities of Hsp70 in mediating its protective effect against hair cell death. Aim 3 is to determine if the protective effect of supporting cell Hsp70 is mediated by secretion of Hsp70 by supporting cells and internalization by hair cells. Aim 4 is to determine the intercellular signals that mediate hair cell-supporting cell communication in response to stress. From a clinical perspective, a clear understanding of the mechanisms underlying hair cell death and survival in response to ototoxic drugs will be critical to the rational design of co-therapies aimed at preventing hearing loss and balance disturbances caused by them. Our data indicate that Hsp70 is protective against hair cell death caused by both aminoglycosides and cisplatin, and thus it represents a potential therapeutic target for both classes of ototoxic drugs. From a basic science perspective, this project addresses the cellular biology of interactions between pro-survival and pro-death signaling in hair cells under stress. In addition, this research program examines the fundamental nature of the interactions between hair cells and supporting cells. PUBLIC HEALTH RELEVANCE: This project is focused on hearing loss caused by exposure to therapeutic drugs that damage the inner ears of at least half a million Americans every year. This project is designed to examine the mechanisms underlying the death and survival of sensory cells in the inner ear exposed to these drugs. Understanding these mechanisms will guide the development of therapies aimed at preventing hearing loss caused by ototoxic drugs.