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. .

大多数聋和前庭疾病由于内部关键细胞的丧失或功能障碍而发生 耳朵，包括毛细胞，支撑细胞和神经元。一旦丢失或受损，这些细胞类型几乎没有或没有 在哺乳动物内耳中再生的能力。近年来，有很多令人兴奋的结果 关于在内源性上皮中产生新毛细胞的方法，通常是通过转化 现有的支持细胞。 Notch信号通路已显示为调节的关键途径 通过称为横向抑制的过程来测定毛细胞或支撑细胞命运。在这个系统中， 表达缺口配体的细胞在周围细胞中激活缺口并防止其采用头发 细胞命运。该信号传导产生了感官镶嵌物，其中每个毛孔都被支撑细胞包围。 抑制Notch可以促进支持细胞向毛细胞的转化，从而为 替换失去或功能失调的毛细胞。但是，Notch信号是一种强大的途径，经常发挥作用 在开发过程中多重角色。我们的初步结果表明，除了选择细胞命运之外，Notch 还通过JAG1配体在人工耳蜗成熟或维持中起着至关重要的作用。具体来说，我们的 结果表明，JAG1删除不会引起细胞命运的改变，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JAG1配体激活Notch是 耳蜗中感觉成熟和/或维护的各个方面所必需的。这里概述的提案 旨在通过（1）确定JAG1在人工耳蜗上皮中的缺失的影响来检验这一假设，（2） 识别介导JAG1效应的细胞类型和受体，以及（3）建立直接和间接靶标 用于JAG1-NOTCH1信号。了解Notch信号在产后成熟和感觉中的作用 维护对于依赖于操纵毛细胞的Notch信号的未来再生疗法至关重要 替代品。 。