Regenerative pathways in the avian cochlea

鸟类耳蜗的再生途径

• 批准号: 10439301
• 负责人: Stefan Heller
• 金额: $ 66.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439301
• 关键词: Adult; Aminoglycosides; Basilar Papilla; Birds; Cell Death; Cells; Chickens; Cochlea; Data; Electrophysiology (science); Epithelium; Equipment and supply inventories; Gene Expression; Generations; Genes; Hair; Hair Cells; Hearing; In Situ; Link; Methodology; Mitotic; Mus; Natural regeneration; Organ; PAR-2 Receptor; Pathway interactions; Regenerative pathway; S phase; Sensory; Sensory Hair; Supporting Cell; Supporting Cell of Organ of Corti; Synapses; Time; Utricle structure; Work; hair cell regeneration; mouse model; novel; planar cell polarity; transcriptomics

Project Summary / Abstract It is known for more than 30 years that supporting cells in the normally quiescent avian hearing organ, the basilar papilla, can respond to sensory hair cell death with S-phase entry, mitotic division, and generation of replacement hair cells. The work proposed here utilizes several methodological advances for an unbiased, comprehensive, and systematic inventorying of changes in gene expression during aminoglycoside-induced hair cell death and in responding supporting cells. Pilot data obtained at multiple time points from single cells isolated from the chicken basilar papilla sensory epithelium revealed that activation of a novel pathway linked to protease-activated receptor-2, PAR2, is essential for S-phase entry of supporting cells and hair cell regeneration. The project puts forward a speci?c hypothesis for the activation pathway, which will be explicitly and thoroughly evaluated. Moreover, the identi?ed e?ector genes for the novel regeneration pathway will be assessed in a new adult mouse model for long-term hair cell loss. Here, the focus is on S-phase entry of mouse utricle and organ of Corti supporting cells four weeks after aminoglycoside-induced hair cell loss. Finally, the project will focus on the characterization of newly regenerated hair cells by reconstructing the temporal transcriptomic changes that happen when the new hair cells mature. In parallel, it is proposed to align transcriptomic data with in situ observations such as hair bundle formation, changes in planar cell polarity, reestablishment of synaptic connections, and electrophysiological features such as mechanoelectrical transduction and electrical tuning.

项目摘要 /摘要 众所周知，已有30多年的历史了，在通常静止的鸟类听力器官中支持细胞， 基底乳头，可以通过S阶段进入，有丝分裂分裂和产生的感觉毛细胞死亡做出反应 替换毛细胞。这里提出的工作利用了几种方法学进步来实现公正的， 氨基糖苷诱导期间基因表达变化的全面和系统库存 毛细胞死亡和反应支持细胞。从单个单元于多个时间点获得的试验数据 从鸡基底乳头感觉上皮中分离出来，发现一种新型途径的激活 对于蛋白酶激活的受体-2 PAR2，对于支持细胞和毛细胞的S相进入至关重要 再生。该项目提出了激活途径的特定假设 并进行了彻底评估。此外，新的再生途径的识别基因将是 在新的成年小鼠模型中评估长期毛细胞损失。在这里，重点是S期进入 氨基糖苷诱导的毛细胞损失四个星期后，小鼠的尿小鼠尿素和器官。 最后，该项目将通过重建新生毛细胞的表征来重构 新毛细胞成熟时发生的时间转录组变化。并行，提议 将转录组数据与原位观察（例如发束形成，平面细胞的变化 极性，突触连接的重新建立以及电生理特征，例如 机械电气转导和电气调整。