Molecular studies of hair cell death

毛细胞死亡的分子研究

• 批准号: 6445061
• 负责人: Alan Gi-Lun Cheng
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6445061
• 关键词: cell death; chickens; cysteine endopeptidases; ear hair cell; enzyme activity; enzyme inhibitors; enzyme mechanism; gentamicins; postdoctoral investigator; tissue /cell culture

DESCRIPTION (provided by applicant): Sensory hair cell death is responsible for the vast majority of human hearing loss and balance disorders. Aging, exposure to noise and therapeutic drugs such as aminoglycosides are all known direct causes of hair cell death. Recent studies have shown cisplatin-and neomycin-induced hair cell death to be caspase-dependent in the mammalian inner ear in vitro. In many cell types across a variety of species, an orderly activation of caspases, a family of cysteine proteases, is a hallmark of cell death. These molecules are segregated into upstream initiators and downstream effectors, where the latter are cleaved and activated by the former. When activated, caspases degrade the cytoskeletal and nuclear scaffolds as well as survival promoting molecules. Although 14 mammalian caspases have been identified to date, the role of specific caspases in mediating hair cell death is unclear. This research project seeks to thoroughly characterize the activation and inhibition of specific caspases in gentamicin-induced auditory hair cell death using an avian in vitro system. The first set of experiments is designed to detect the activated forms of specific caspases in hair cells damaged by aminoglycosides. The next set of experiments investigates whether inhibition of upstream caspases prevents activation of the downstream members. The last set of experiments focuses on evaluating the effects of caspase inhibitors on hair cell survival after gentamicin exposure. Knowledge gained from these studies will provide new insights on key mediators in hair cell death and contribute to the development of better otoprotective therapies.

描述（由申请人提供）：感觉毛细胞死亡是负责的 对于绝大多数人的听力损失和平衡障碍。老化， 暴露于噪声和治疗药物（例如氨基糖苷）都是 已知的直接原因导致毛细胞死亡。最近的研究表明顺铂及其 新霉素诱导的毛细胞死亡是caspase依赖于哺乳动物的 体外内耳。在各种物种的许多细胞类型中，有序 激活半胱氨酸蛋白酶家族的胱天蛋白酶是细胞的标志 死亡。这些分子被隔离为上游启动器和下游 效应子，后者被前者裂解和激活。什么时候 激活的，caspase也会降解细胞骨架和核支架 作为促进分子的生存。虽然有14个哺乳动物胱天蛋白酶 迄今为止确定，特定胱天蛋白酶在介导毛细胞中的作用 死亡尚不清楚。该研究项目旨在彻底表征 庆大霉素引起的听觉中的特定胱天蛋白酶的激活和抑制 使用禽类体外系统的毛细胞死亡。第一组实验 旨在检测毛细胞中特定胱天蛋白酶的活化形式 被氨基糖苷损坏。下一组实验调查了是否 抑制上游胱天蛋白酶阻止下游成员的激活。 最后一组实验的重点是评估caspase的影响 庆大霉素暴露后毛细胞存活的抑制剂。知识获得了 从这些研究中将提供有关毛细胞关键介体的新见解 死亡并有助于发展更好的眼科疗法。