Mechanisms of Sensory Hair Cell Death and Survival

感觉毛细胞死亡和生存的机制

• 批准号: 7094066
• 负责人: Lisa L Cunningham
• 金额: $ 35.64万
• 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/7094066
• 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）：感觉毛细胞对噪音、衰老和一些治疗药物引起的死亡高度敏感。两类主要的耳毒性药物是氨基糖苷类抗生素和抗肿瘤剂顺铂。我们计划利用成年小鼠椭圆囊的独特体外制备方法，使我们能够在分子水平上检查耳毒性毛细胞死亡和存活的潜在机制。了解这些细胞机制对于设计旨在预防或逆转听力损失的疗法至关重要。响应细胞应激而诱导热休克蛋白（HSP）是一种普遍存在且高度保守的反应，可以显着抑制某些系统中的细胞凋亡。 HSP 的诱导发生在毛细胞中，以响应各种刺激。然而，尚无关于 HSP 对耳毒性药物诱导的毛细胞死亡影响的研究。更重要的是，没有关于热休克蛋白和毛细胞中的凋亡蛋白之间响应任何刺激的细胞相互作用的数据。我们的初步数据表明，体外热休克治疗可抑制新霉素和顺铂暴露引起的毛细胞死亡。本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 介导的特定细胞凋亡信号通路抑制的结果。提出四组实验：1)。旨在检查介导顺铂与氨基糖苷类诱导的毛细胞死亡的分子机制之间的相似性和差异。 2）。确定热休克治疗是否足以引起耳毒性药物浓度与毛细胞存活之间剂量反应关系的转变。 3）。确定HSP-70的诱导对于热休克对耳毒性毛细胞凋亡的保护作用是否是必要和充分的。 4).研究暴露于耳毒性药物的毛细胞中热休克蛋白与凋亡蛋白之间的相互作用。