MECHANISMS OF SENSORY HAIR CELL DEATH

感觉毛细胞死亡的机制

基本信息

批准号：
6292926
负责人：
Lisa L Cunningham
金额：
$ 3.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-12-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6292926
关键词：
cell death cysteine endopeptidases ear hair cell enzyme activity enzyme inhibitors laboratory mouse labyrinth disorder neomycin neurotoxicology ototoxin tissue /cell culture

项目摘要

Vertebrate sensory hair cells are sensitive to damage from a variety of genetic and environmental factors, including exposure to aminoglycoside antibiotics. Exposure to these antibiotics results in death of sensory hair cells. In mammals the loss of hair cells can result in permanent hearing loss and/or balance disturbances. Recent evidence indicates that exposure to aminoglycosides activates an intrinsic cell death pathway in hair cells. This cascade involves activation of a family of cysteine proteases called caspases. Caspase activation is the hallmark of programmed cell death in other systems, and different caspases are activated in response to different cell death-promoting stimuli. The overall goal of the proposed research is to utilize an in vitro model of mammalian sensory hair cell ototoxicity to determine the involvement of specific caspases in aminoglycoside-induced hair cell death. In the first set of experiments, I will determine which caspases are activated in sensory hair cells in response to aminoglycoside exposure and evaluate whether the cells activating caspases are subsequently dying. The second set of experiments will focus on determining which upstream caspases mediate activation of specific downstream caspases in hair cells exposed to aminoglycosides. Such an understanding of the order of caspase activation is an essential step toward understanding the signaling cascade that takes place in a damaged hair cell. The third set of experiments is designed to determine which individual caspases are necessary for aminoglycoside-induced programmed cell death in hair cells. Taken together, the experiments are designed to provide the first examination of the cascade of caspase activation in hair cells beginning with the cell death trigger and proceeding through the actual execution of the cell.

脊椎动物的感觉毛细胞对多种遗传和环境因素的损害敏感，包括暴露于氨基糖苷抗生素。暴露于这些抗生素会导致感觉毛细胞死亡。在哺乳动物中，毛细胞的丧失会导致永久性听力损失和/或平衡干扰。最近的证据表明，暴露于氨基糖苷会激活毛细胞中固有的细胞死亡途径。该级联反应涉及激活一个称为胱天蛋白酶的半胱氨酸蛋白酶家族。 caspase激活是其他系统中编程细胞死亡的标志，并且因响应不同的细胞死亡刺激而激活不同的胱天蛋白酶。拟议研究的总体目标是利用哺乳动物感觉毛细胞耳毒性的体外模型来确定特定caspase在氨基糖苷诱导的毛细胞死亡中的参与。在第一组实验中，我将确定哪些胱天蛋白酶在响应氨基糖苷暴露的情况下激活了在感觉毛细胞中，并评估激活胱天蛋白酶的细胞是否随后死亡。第二组实验将集中于确定哪些上游胱天蛋白酶介导暴露于氨基糖苷的毛细胞中特定的下游胱天蛋白酶的激活。对胱天蛋白酶激活顺序的这种理解是理解在受损的毛细胞中发生的信号传导级联反应的重要步骤。第三组实验旨在确定哪些单个胱天蛋白酶对于氨基糖苷诱导的毛细胞中的编程细胞死亡是必需的。综上所述，实验旨在提供对毛细胞中级联反应激活的首次检查，从细胞死亡触发开始，并通过细胞的实际执行进行进行。