Genetics of Zebrafish Hair Cell Toxicity

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（内耳的受体细胞）的死亡。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造成的损害高度敏感。然而，在人类和实验室动物中，这些挑战对内耳的结构和功能结果存在巨大的差异，并且大量突变直接影响毛细胞的活力，或改变对耳毒性的易感性。本文提出的研究计划的目标是：A）更好地定义在暴露于潜在的耳毒性剂之后控制毛细胞死亡和存活的细胞和分子级联; B）利用斑马鱼的遗传潜能和侧线神经瘤的可接近性来鉴定和表征当受到耳毒性剂挑战时影响毛细胞活力的基因;和C）使用侧线系统快速筛选保护免受损害的小分子/药物。提出了四组实验：1）我们将从分子水平上表征5种已经鉴定的赋予氨基糖苷类抗生素抗性的突变; 2）我们将使用毛细胞死亡的化学和遗传修饰剂来鉴定导致毛细胞死亡的不同途径; 3）我们将筛选改变对氨基糖苷类抗生素反应的新基因和药物;以及4）我们将确定我们从斑马鱼侧线系统的发现在多大程度上延伸到哺乳动物系统。在美国，超过3100万成年人有听力问题。我们的研究将揭示耳朵的声音感知细胞是如何受损的，确定可能导致听力损失变化的基因，并找到可能有助于预防听力损失的药物。

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.