Notch Signaling during Organ of Corti Maturation and Maintenance

柯蒂器官成熟和维持过程中的Notch信号传导

• 批准号: 10338132
• 负责人: Amy Kiernan
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10338132
• 关键词: Adopted; Adult; Alleles; Auditory Brainstem Responses; Cell Maturation; Cells; Cochlea; Complex; Data; Defect; Development; Disease; Down-Regulation; Ear; Embryo; Ensure; Epithelial; Functional disorder; Future; Genes; Hair Cells; Hearing; Histologic; Human; Impairment; Inner Hair Cells; Labyrinth; Lateral; Ligands; Maintenance; Mammals; Mediating; Membrane; Molecular; Mosaicism; Natural regeneration; Neonatal; Neurons; Notch Signaling Pathway; Organ of Corti; Pathology; Pathway interactions; Pattern; Play; Process; Receptor Cell; Role; Sensory; Signal Pathway; Signal Transduction; Supporting Cell; System; Testing; Therapeutic Intervention; Up-Regulation; auditory neuropathy; cell type; deafness; experimental study; hearing impairment; mouse model; mutant; notch protein; novel; otoacoustic emission; postnatal; prevent; receptor; regenerative therapy; transcriptome sequencing; transdifferentiation

The majority of deafness and vestibular disorders occur due to loss or dysfunction of critical cells in the inner ear, including hair cells, supporting cells and neurons. Once lost or impaired, these cell types show little or no ability to regenerate in the mammalian inner ear. In recent years, there have been a number of exciting results regarding approaches to generate new hair cells in the endogenous epithelium, often through transformation of existing supporting cells. The Notch signaling pathway has been shown to be a key pathway in regulating the determination of the hair cell or supporting cell fate, through a process called lateral inhibition. In this system, cells expressing the Notch ligand activate Notch in the surrounding cells and prevent them from adopting a hair cell fate. This signaling creates the sensory mosaic in which each hair cell is surrounded by supporting cells. Inhibition of Notch can promote the conversion of supporting cells into hair cells, providing an avenue for replacing lost or dysfunctional hair cells. However, Notch signaling is a powerful pathway that often plays multiple roles during development. Our preliminary results indicate that in addition to cell fate choices, Notch also plays an essential role in cochlear maturation or maintenance via the JAG1 ligand. Specifically, our results demonstrate that JAG1 deletion does not cause cell fate alterations but instead leads to hearing deficits resembling auditory neuropathy in humans. We hypothesize that activation of Notch via the JAG1 ligand is required for aspects of sensory maturation and/or maintenance in the cochlea. The proposal outlined here aims to test this hypothesis, by (1) establishing the effects of deletion of Jag1 in the cochlear epithelium, (2) identifying the cell type and receptors that mediate JAG1 effects, and (3) establishing direct and indirect targets for JAG1-Notch1 signaling. Understanding the role of Notch signaling in postnatal maturation and sensory maintenance is essential for future regenerative therapies that rely on manipulating Notch signaling for hair cell replacement. .

大多数耳聋和前庭障碍的发生是由于内皮层关键细胞的丢失或功能障碍。 耳，包括毛细胞，支持细胞和神经元。一旦丢失或受损，这些细胞类型显示很少或没有 哺乳动物内耳的再生能力。近年来，有许多令人兴奋的结果， 关于在内源性上皮中产生新的毛细胞的方法，通常通过转化 现有的支持细胞。Notch信号通路已被证明是调节细胞凋亡的关键通路。 决定毛细胞或支持细胞的命运，通过一个过程称为侧抑制。在这个系统中， 表达Notch配体的细胞激活周围细胞中的Notch并阻止它们采用毛发 细胞命运这种信号传导创造了感觉镶嵌，其中每个毛细胞都被支持细胞包围。 抑制Notch可以促进支持细胞向毛细胞的转化，为毛细胞的分化提供了途径。 替代失去或功能失调的毛细胞。然而，Notch信号传导是一种强大的途径， 在发展过程中扮演多个角色。我们的初步结果表明，除了细胞命运的选择，Notch 也通过JAG 1配体在耳蜗成熟或维持中起重要作用。具体来说，我们 结果表明，JAG 1缺失不会导致细胞命运改变，而是导致听力缺陷 类似于人类的听觉神经病。我们假设通过JAG 1配体激活Notch是 这是耳蜗感觉成熟和/或维持方面所需的。这里概述的提案 旨在通过以下方式检验这一假设：（1）确定耳蜗上皮中Jag 1缺失的影响，（2） 鉴定介导JAG 1效应的细胞类型和受体，以及（3）建立直接和间接靶点 用于JAG 1-Notch 1信号传导。理解Notch信号在出生后成熟和感觉神经中的作用 维持对于依赖于操纵毛细胞Notch信号传导的未来再生疗法至关重要。 更换. .