Screens for modulators of hair cell regeneration

描述（由申请人提供）：毛细胞对环境损伤（如过度噪音或化学品暴露）敏感，导致其死亡。不幸的是，它们在人类身上的损失是不可逆转的。在这个应用中，我们建议使用斑马鱼的机械感觉侧线系统来研究毛细胞再生的调节。侧线毛细胞与内耳毛细胞具有相同的细胞和分子特性，但易于可视化和操作。我们提出了两个筛选：寻找改变毛细胞再生的突变，并确定再生的小分子调节剂。我们的初步研究表明，这两个屏幕是可行的。在最初的筛选中，我们已经确定了8种改变再生的突变和两种增强毛细胞替代的化合物。我们建议详细描述这些遗传和小分子调节剂改变毛细胞再生的机制。我们也将绘制突变图谱，开始鉴定突变表型背后的分子损伤。这些研究将帮助我们了解控制斑马鱼毛细胞再生的调控途径，并可能揭示哺乳动物中不再允许再生发生的步骤。 公共卫生相关性：耳毛细胞的损伤和损失是耳聋的主要原因，不幸的是，它们不能再生。斑马鱼保留了毛细胞受损后再生的能力。这项提案中的工作旨在确定调节斑马鱼毛细胞再生的基因，并发现调节这一过程的药物，希望未来能够治疗听力损失。

DESCRIPTION (provided by applicant): Hair cells are sensitive to environmental insults such as excessive noise or chemical exposure, resulting in their death. Unfortunately, their loss in humans is irreversible. In this application, we propose to use the zebrafish mechanosensory lateral line system to study the regulation of hair cell regeneration. Lateral line hair cells share cellular and molecular properties with hair cells of the inner ear, yet are easily accessible to visualization and manipulation. We propose two screens: to search for mutations that alter hair cell regeneration and to identify small molecule regulators of regeneration. Our preliminary studies show that both screens are feasible. In initial screens, we have identified 8 mutations that alter regeneration and two compounds that enhance hair cell replacement. We propose to characterize in detail the mechanisms by which hair cell regeneration is altered by these genetic and small molecule modulators. We will also map mutations to begin identification of the molecular lesions that underlie mutant phenotypes. These studies will help us understand the regulatory pathways that control zebrafish hair cell regeneration, and may reveal the steps altered in mammals that no longer allow regeneration to occur. PUBLIC HEALTH RELEVANCE: Damage and loss of hair cells in the ear is a leading cause of deafness, and unfortunately they cannot grow back. Zebrafish have retained the ability to regenerate their hair cells after damage. Work in this proposal seeks to identify genes that regulate zebrafish hair cell regeneration and discover drugs that modulate this process, with the hopes for future therapies for hearing loss.