Modulation of hair cell toxicity in zebrafish

斑马鱼毛细胞毒性的调节

基本信息

批准号：
6836732
负责人：
KELLY N OWENS
金额：
$ 5.65万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-25 至 2006-06-24
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Loss of sensory hair cells is a major cause of hearing impairment and can arise from both genetic and environmental causes including noise trauma, aging, and drug exposure. The overall objective of this application is to investigate the mechanism of aminoglycoside drug toxicity in hair cells. This research will test the hypothesis that perturbation of proteins which are direct or indirect targets of aminoglycosides will alter the degree of hair cell death using the zebrafish lateral line as a model system. Two approaches are used to define components modulating aminoglycoside toxicity: physiological alteration of hair cells in wildtype zebrafish and isolation of mutants with altered aminoglycoside response. The specific aims of this application are to: 1) test whether disruption of mitochondrial function alters aminoglycoside response; 2) determine the molecular nature of the zebrafish sentinel mutation that exhibits aminoglycoside resistance; and 3) identify new mutations with sensitivity or resistance to aminoglycoside hair cell loss. The long term goal of this research to identify pathways which may underlie other less experimentally tractable forms of hair cell loss, such as age or noise related hair cell loss, and to suggest targets for intervention during drug treatment.

描述（由申请人提供）：感官毛细胞的丧失是听力障碍的主要原因，可能源于遗传和环境原因，包括噪声创伤，衰老和药物暴露。该应用的总体目的是研究毛细胞中氨基糖苷药物毒性的机制。这项研究将检验以下假设：氨基糖苷的直接或间接靶标的蛋白质将使用斑马鱼侧线作为模型系统改变毛细胞死亡的程度。使用两种方法来定义调节氨基糖苷毒性的成分：野生型斑马鱼中毛细胞的生理改变，以及随着氨基糖苷反应改变的突变体的分离。本应用的具体目的是：1）测试线粒体功能的破坏是否会改变氨基糖苷的响应； 2）确定表现出氨基糖苷耐药性的斑马鱼前哨突变的分子特性； 3）确定具有敏感性或对氨基糖苷毛细胞损失的新突变。这项研究的长期目标是确定可能是其他实验性较低的毛细胞损失形式（例如年龄或噪声相关的毛细胞损失）的基础的途径，并建议在药物治疗期间进行干预目标。