Competence of support cells to form hair cells in the mammalian inner ear

支持细胞在哺乳动物内耳中形成毛细胞的能力

• 批准号: 10611885
• 负责人: Olivia Mary Bermingham-McDonogh
• 金额: $ 40.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611885
• 关键词: Adult; Affect; Age; Amphibia; Applications Grants; Auditory; Basilar Papilla; Birds; Cells; Chromatin; Cochlea; Competence; Corwin; Crista ampullaris; Data; Development; Dissociation; Epigenetic Process; Epithelium; Fishes; Gene Expression; Gene Expression Profile; Genes; Grant; Hair Cells; Head; Human; Image; Labyrinth; Mammalian Cell; Mammals; Methods; Mitotic; Molecular; Mus; Natural regeneration; Newborn Infant; Organ; Organ of Corti; Outer Hair Cells; Pathway interactions; Persons; Population; Process; Proliferating; Regenerative response; Reporter; Reporting; Resolution; Rotation; Semicircular canal structure; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Supporting Cell; System; Techniques; Testing; Time; Time Study; Transgenic Mice; Transgenic Organisms; Vertebrates; base; equilibration disorder; experimental study; gaze; hair cell regeneration; hearing impairment; inhibitor; lateral line; notch protein; overexpression; postnatal; regenerative; single-cell RNA sequencing; transdifferentiation

Summary/Abstract In humans, loss of the hair cells in the inner ear leads to hearing and balance impairment, since these cells do not regenerate. By contrast, in non-mammalian vertebrates, like birds and fish, damaged auditory hair cells are regenerated very efficiently from the surrounding supporting cells. The ability of support cells to give rise to hair cells through transdifferentiation was first demonstrated by Corwin in the amphibian lateral line, by direct observation using time-lapse imaging, but more indirect methods also found a similar process to occur in bird basilar papilla. These results together suggest that the problem of hair cell regeneration in the inner ear of the mammal can be summarized in two fundamental questions: (1) What causes the loss in proliferation of support cells following damage and (2) what limits the transdifferentiation of the support cells to new hair cells? In this grant application we aim to study what are the factors that limit regeneration in the vestibular system of the mammal. We will use various transgenic strains to activate pathways that may lead to stimulation of hair cell regeneration. We will specifically direct our studies towards the crista (the sensory regions at the base of the three semicircular canals) that detect head rotation in the three ordinal planes. As the population ages balance disorders become more prevalent and this organ is particularly important for maintaining gaze. The cristae have been understudied at the molecular level to date and we have recently developed a culture method and are using advanced molecular techniques to elucidate changes in the competence of crista support cells to generate hair cells.

摘要/摘要 在人类中，内耳中毛细胞的丧失会导致听力和平衡障碍，因为这些细胞确实 不再再生。相比之下，在非哺乳动物脊椎动物（如鸟类和鱼类）中，受损的听觉毛细胞是 从周围的支撑细胞中非常有效地再生。支持细胞产生头发的能力 Corwin首先通过直接证明了两栖动物的细胞。 使用延时成像观察，但更多的间接方法也发现了与鸟类发生的类似过程 基底乳头。这些结果在一起表明，毛细胞再生的问题 可以在两个基本问题中总结哺乳动物：（1）是什么导致支持的损失 损坏后的细胞和（2）是什么限制了支持细胞对新毛细胞的转变？在这个 我们旨在研究限制在前庭系统中再生的因素是什么 哺乳动物。我们将使用各种转基因菌株激活可能导致毛细胞刺激的途径 再生。我们将专门将我们的研究转向Crista（底部的感觉区域 三个半圆形管）检测三个顺序平面中的头部旋转。随着人口年龄的平衡 疾病变得更加普遍，该器官对于保持凝视尤其重要。 cristae 迄今已在分子水平上进行了研究，我们最近开发了一种培养方法和 正在使用高级分子技术来阐明Crista支持细胞能力的变化 产生毛细胞。