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

p53 和氨基糖苷类诱导斑马鱼侧线毛细胞死亡

基本信息

批准号：
8374110
负责人：
ALLISON B COFFIN
金额：
$ 14.35万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374110
关键词：
Acute Affect Aging-Related Process Agonist Aminoglycoside Antibiotics Aminoglycosides Bax protein Biological Assay Biological Models Biological Preservation Cell Death Cell Death Process Cell Nucleus Cells Cessation of life Cytoprotection Drug Exposure Equilibrium Event Fishes Future Genetic Genetic Transcription Gentamicins Goals Hair Cells Hearing Labyrinth Measures Mediating Membrane Potentials Mitochondria Neomycin Noise Nuclear Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Protein p53 Proteins Reporter Research Response Elements Role Sensory Sensory Hair Signal Pathway Signal Transduction System Testing Time Toxic effect Toxicant exposure Toxin Transactivation Translations Tumor Suppressor Proteins Zebrafish base cell injury design gain of function hearing impairment in vivo Model inhibitor/antagonist lateral line loss of function mitochondrial membrane mutant prevent programs public health relevance research study response small molecule

项目摘要

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.

描述（由申请人提供）：听力损失影响着全世界数百万人，通常是由于内耳感觉毛细胞死亡所致。毛细胞因噪音暴露、药物损伤以及衰老过程中逐渐丧失。拟议研究的总体目标是进一步了解因药物损伤（特别是氨基糖苷类抗生素引起的损伤）导致毛细胞死亡的细胞内信号传导途径。这项研究将使用斑马鱼侧线，这是一种强大的体内模型系统，用于实时毛细胞死亡和保护研究。我们之前的研究表明，密切相关的氨基糖苷类新霉素和庆大霉素通过至少两个不同且部分重叠的细胞死亡过程损伤毛细胞。拟议研究的具体目标是了解区分这些细胞死亡过程的细胞内事件，重点关注肿瘤抑制蛋白 p53 在该系统毛细胞死亡过程中的多方面作用。这项研究将检验这样的假设：斑马鱼侧线中氨基糖苷类诱导的毛细胞死亡依赖于不同的 p53 功能，新霉素或短期庆大霉素暴露引起的急性损伤需要 p53 在线粒体上的直接活性，并且较慢庆大霉素诱导的损伤依赖于细胞核中 p53 转录活性。具体而言，拟议项目将 1) 测试氨基糖苷类诱导的毛细胞死亡中对 p53 的需求，2) 表征氨基糖苷类暴露期间直接 p53 线粒体活性的参与情况，以及 3) 测试氨基糖苷类诱导的毛发过程中对 p53 核活性的需求细胞损伤。更全面地了解不同毛细胞毒素激活的特定细胞死亡途径将使我们能够更直接地针对潜在的保护性疗法，从而使接受耳毒性药物治疗的患者能够保留听力。