Genetics of Zebrafish Hair Cell Toxicity

斑马鱼毛细胞毒性的遗传学

基本信息

批准号：
8116123
负责人：
David W Raible
金额：
$ 7.8万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116123
关键词：
Adult Aging Aminoglycoside Antibiotics Aminoglycoside resistance Aminoglycosides Anions Bicarbonates Cavia Cell Death Cell physiology Cells Cessation of life Chemicals Chromosome Mapping Cisplatin Cochlea Ear Event Exposure to FDA approved Funding Genes Genetic Gentamicins Goals Hair Cells Hearing Human Image Laboratory Animals Labyrinth Libraries Maps Mitochondria Modeling Molecular Mus Mutation Neomycin Pathway interactions Pharmaceutical Preparations Physiological Predisposition Prevention Protective Agents Receptor Cell Research Resistance Screening procedure Sensory Hair Sentinel Sorting - Cell Movement Stress Structure Swimming System Testing Therapeutic Therapeutic Intervention Toxic Environmental Substances Toxic effect Utricle structure Validation Zebrafish cell injury chemical genetics equilibration disorder functional outcomes genetic manipulation hearing impairment in vivo indexing lateral line mutant neuromast novel ototoxicity programs research study response sensory system small molecule sound toxicant uptake

项目摘要

DESCRIPTION (provided by applicant): The vast majority of hearing and balance impairments are thought to be due to death of sensory hair cells, the receptor cells of the inner ear. These cells are unusually metabolically active and hypersensitive to damage from overstimulation, some therapeutic drugs and environmental toxins, and aging. However, there is enormous variability in structural and functional outcomes of these challenges to the inner ear among both humans and laboratory animals, and a large number of mutations either directly influence the viability of hair cells, or alter susceptibility to ototoxicity. The goals of the research program proposed herein are: A) to better define the cellular and molecular cascades that control hair cell death and survival following exposure to potentially ototoxic agents; B) to use the genetic potential of the zebrafish and the accessibility of the lateral line neuromasts to identify and characterize genes that influence the viability of hair cells when challenged by ototoxic agents; and C) to employ the lateral line system to rapidly screen for small molecules/drugs that protect against damage. Four groups of experiments are proposed: 1) We will molecularly characterize 5 already identified mutations that confer resistance to aminoglycoside antibiotics; 2) We will identify distinct pathways resulting in hair cell death using chemical and genetic modifiers of hair cell death; 3) We will screen for new genes and drugs that alter the response to aminoglycosides; and 4) We will determine to what degree our findings from the zebrafish lateral line system extend to mammalian systems. In the US, over 31 million adults have trouble hearing. Our research will reveal how the sound-sensing cells of the ear are damaged, identify genes that may underlie the variability in hearing loss, and find drugs that may help in its prevention.

描述（由申请人提供）：绝大多数听力和平衡障碍被认为是由于感觉毛细胞的死亡，即内耳的受体细胞。这些细胞异常活跃，对过度刺激，某些治疗药物和环境毒素以及衰老而受到损害过敏。但是，这些挑战在人类和实验动物中对内耳挑战的结构和功能结果存在巨大变化，并且大量突变要么直接影响毛细胞的生存能力，要么改变了对耳毒性的敏感性。本文提出的研究计划的目标是：a）更好地定义暴露于潜在的耳毒剂后控制毛细胞死亡和存活的细胞和分子级联反应； b）使用斑马鱼的遗传潜力和侧向线神经瘤的可及性来识别和表征在受耳毒剂挑战时影响毛细胞生存力的基因； c）使用横向线系统快速筛选防止损害的小分子/药物。提出了四组实验：1）我们将分子表征5个已经鉴定出对氨基糖苷抗生素抗性的突变； 2）我们将使用毛细胞死亡的化学和遗传修饰剂来确定导致毛细胞死亡的不同途径； 3）我们将筛选出改变对氨基糖苷反应的新基因和药物； 4）我们将确定斑马鱼侧线系统的发现扩展到哺乳动物系统的程度。在美国，超过3100万成年人的听力困难。我们的研究将揭示耳朵的发声细胞如何受损，确定可能是听力损失变异性的基因，并找到可能有助于预防的药物。