Mechanisms of Sensory Hair Cell Death and Survival

感觉毛细胞死亡和生存的机制

• 批准号: 6954791
• 负责人: Lisa L Cunningham
• 金额: $ 36.5万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954791
• 关键词: aminoglycoside antibiotics; antineoplastics; apoptosis; biological signal transduction; cell death; cisplatin; cytotoxicity; dosage; drug adverse effect; ear hair cell; heat shock proteins; laboratory mouse; molecular pathology; pathologic process; protein structure function

DESCRIPTION (provided by applicant): Sensory hair cells are hypersensitive to death induced by noise, aging, and some therapeutic drugs. Two major classes of ototoxic drugs are the aminoglycoside antibiotics and the antineoplastic agent cisplatin. We plan to take advantage of a unique in vitro preparation of the adult mouse utricle that allows us to examine the rrechanisms underlying ototoxic hair cell death and survival at the molecular level. Understanding these cellular mechanisms will be critical for the design of therapies aimed at preventing or reversing hearing loss. The induction of heat shock proteins (HSPs) in response to cellular stress is a ubiquitous and highlyconserved response that can significantly inhibit apoptosis in some systems. Induction of HSPs occurs in hair cells in response to a variety of stimuli. However, there are no studies on the effects of HSPs on ototoxic drug-induced hair cell death. More importantly, there are no data available regarding the cellular interactions between HSPs and apoptotic proteins in hair cells in response to any stimulus. Our preliminary data demonstrate that in vitro heat shock treatment inhibits hair cell death in response to both neomycin and cisplatin exposure. The experiments in this proposal are designed to test the hypothesis that the protective effect of heat shock against ototoxic drug-induced hair cell death is the result of HSP-mediated inhibition of specific apoptotic signaling pathways. Four groups of experiments are proposed: 1). To examine the similarities and differences between the molecular mechanisms mediating cisplatin- vs. aminoglycoside-induced hair cell death. 2). To determine whether heat shock treatment is sufficient to induce a shift in the dose-response relationship between ototcxic drug concentration and hair cell survival. 3). To determine whether induction of HSP-70 is necessary and sufficient for the protective effect of heat shock against ototoxic hair cell apoptosis. 4). To investigate the interactions between HSPs and apoptotic proteins in hair cells exposed to ototoxic drugs.

描述（由申请人提供）：感官毛细胞对噪声，衰老和某些治疗药物引起的死亡过敏。两种主要类耳毒性药物是氨基糖苷抗生素和抗肿瘤剂顺铂。我们计划利用成年小鼠尿素的独特体外制备，这使我们能够检查耳毒性毛细胞死亡和分子水平生存的基础机制。了解这些细胞机制对于旨在防止或逆转听力损失的疗法设计至关重要。热休克蛋白（HSP）响应细胞应激的诱导是一种无处不在且高度严格的反应，可以显着抑制某些系统中的凋亡。 HSP的诱导发生在毛细胞中，响应各种刺激。但是，没有关于HSP对耳毒性药物诱导毛细胞死亡的影响的研究。更重要的是，尚无有关HSP与毛细胞中HSP与凋亡蛋白之间细胞相互作用的可用数据，以响应任何刺激。我们的初步数据表明，体外热休克处理抑制了新霉素和顺铂暴露的毛细胞死亡。该提案中的实验旨在检验以下假设：热休克对耳毒性药物诱导的毛细胞死亡的保护作用是HSP介导的特定凋亡信号传导途径的抑制作用。提出了四组实验：1）。检查介导顺铂与氨基糖苷诱导的毛细胞死亡的分子机制之间的相似性和差异。 2）。确定热休克处理是否足以诱导Ototc毒性药物浓度和毛细胞存活之间的剂量反应关系转移。 3）。确定HSP-70的诱导是否是必要且足以使热休克对耳毒性毛细胞凋亡的保护作用。 4）。研究暴露于耳毒性药物的毛细胞中HSP和凋亡蛋白之间的相互作用。