p53 and aminoglycoside-induced hair cell death in the zebrafish lateral line

描述（由申请人提供）：听力损失影响着全世界数百万人，通常是由内耳感觉毛细胞死亡引起的。毛细胞由于噪音暴露、药物损伤以及在衰老过程中逐渐丧失。拟议研究的总体目标是进一步了解毛细胞因药物损伤而死亡的细胞内信号通路，特别是氨基糖苷类抗生素引起的损伤。本研究将使用斑马鱼侧线，一个强大的实时毛细胞死亡和保护研究的体内模型系统。我们之前的研究表明，密切相关的氨基糖苷新霉素和庆大霉素通过至少两个不同的和部分重叠的细胞死亡过程损伤毛细胞。该研究的具体目标是了解细胞内事件，区分这些细胞死亡过程，重点关注肿瘤抑制蛋白p53在该系统中毛细胞死亡过程中的多方面作用。本研究将验证氨基糖苷诱导的斑马鱼侧线毛细胞死亡依赖于多种p53功能的假设，新霉素或短期庆大霉素暴露引起的急性损伤需要线粒体中p53的直接活性，而庆大霉素诱导的损伤的较慢阶段依赖于细胞核中p53的转录活性。具体来说，拟议的项目将1)测试氨基糖苷诱导的毛细胞死亡对p53的需求，2)表征氨基糖苷暴露期间p53直接线粒体活性的参与，以及3)测试氨基糖苷诱导的毛细胞损伤期间p53核活性的需求。对不同毛细胞毒素激活的特定细胞死亡途径的更彻底的了解将使我们能够更直接地针对潜在的保护疗法，从而允许耳毒性药物治疗患者的听力保护。

DESCRIPTION (provided by applicant): Hearing loss affects millions of people worldwide and often results from death of the sensory hair cells in the inner ear. Hair cells are lost due to noise exposure, drug damage, and progressively during the aging process. The overall goal of the proposed research is to further understand the intracellular signaling pathways responsible for hair cell death due to drug damage, specifically damage caused by the aminoglycoside antibiotics. This research will use the zebrafish lateral line, a powerful in vivo model system for real-time hair cell death and protection studies. Our previous research has demonstrated that the closely related aminoglycosides neomycin and gentamicin damage hair cells via at least two distinct and partially overlapping cell death processes. The specific goal of the proposed research is to understand the intracellular events that differentiate these cell death processes with a focus on the multifaceted role of the tumor suppressor protein p53 during hair cell death in this system. This research will test the hypothesis that aminoglycoside-induced hair cell death in the zebrafish lateral line is dependent on diverse p53 functions, with the acute damage caused by neomycin or short-term gentamicin exposure requiring direct activity of p53 at the mitochondria, and the slower phase of gentamicin-induced damage dependent on p53 transcriptional activity in the nucleus. Specifically, the proposed project will 1) test the requirement for p53 in aminoglycoside-induced hair cell death, 2) characterize the involvement of direct p53 mitochondrial activity during aminoglycoside exposure, and 3) test the requirement for p53 nuclear activity during aminoglycoside-induced hair cell damage. A more thorough understanding of the specific cell death pathways activated by different hair cell toxins will allow us to more directly target potential protective therapies, allowing for hearing preservation in patients treated with ototoxic drugs. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to better understand hearing loss so that we may prevent it. This research uses zebrafish, which have sensory cells that are similar to the cells that allow us to hear, in order to study how these cells are damaged due to drugs. Understanding how these sensory cells are damaged will help us design strategies to protect them, hopefully preventing hearing loss.