Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance

听觉支持细胞分化和维持中的Notch信号通路

基本信息

批准号：
9759912
负责人：
ANGELIKA DOETZLHOFER
金额：
$ 34.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759912
关键词：
Address Animals Auditory Auditory Physiology Cell Differentiation process Cell Maintenance Cell Maturation Cell Survival Cell physiology Cellular Morphology Cochlea Cues Data Defect Development Epithelium Frequencies Functional disorder Future Gene Expression Generations Genetic Transcription Goals Hair Cells Homeostasis Human INHBA gene Instruction Lead Ligands Light Mammals Measurement Mediating Molecular Morphology Mus NOTCH3 gene Natural regeneration Neurons Notch Signaling Pathway Outer Hair Cells Physiology Play Production RNA-Binding Proteins Regenerative response Replacement Therapy Repression Role Sensory Signal Transduction Stimulus Structure Supporting Cell Tissues Transcription Alteration Transgenic Mice Vertebrates WNT Signaling Pathway activin A base biophysical properties cell injury deafness experimental study gamma secretase gene function hair cell regeneration hearing impairment in vivo regeneration inhibitor/antagonist insight mutant nerve supply new therapeutic target notch protein novel novel therapeutic intervention overexpression postnatal ranpirnase receptor regenerative repaired response transcriptome

项目摘要

Project summary Auditory supporting cells (SCs) are essential for the proper development, survival and function of mechano- sensory hair cells (HCs) and their innervating neurons. Defects in the biophysical properties or function of SCs result in auditory dysfunction and hearing loss. Despite their importance the molecular mechanisms that control their development and function are largely unknown. A main objective of our proposed study is to uncover the molecular mechanisms that guide auditory SCs development and function. We recently uncovered that Notch signaling instructs SC development in the murine cochlea. Here in this proposed study we will determine the Notch ligand(s) and receptor(s) that control SC differentiation and survival (aim1) as well characterize potential novel roles for Notch signaling and its targets in SC-guided cochlear innervation and auditory function (aim2). Our proposed studies will advance our understanding of how Notch signaling operates in differentiating SCs as wells as provide new insights into how SCs guide neuronal innervation as well as control cochlear homeostasis. A second major objective of our proposed study is to uncover the molecular mechanisms that control the developmental decline of SCs plasticity in the mammalian cochlea. HC loss in mammals is permanent and is a leading cause for deafness in humans. In non- mammalian vertebrates SCs regenerate lost HCs throughout the lifetime of the animal. In mammals, young immature SCs can be coaxed into regenerating lost HCs by inhibiting Notch signaling or over-stimulation of wnt signaling; however, the ability of murine auditory SC to respond to such regenerative stimuli rapidly declines after the first postnatal week. We recently uncovered that the RNA binding protein LIN28B enhances HC production in the immature cochlea in response to Notch signaling. In aim3 we will investigate how LIN28B/let- 7 axis modifies the regenerative response of the immature SCs, as well as address whether LIN28B re- expression in mature SCs enhances their ability to respond to Notch inhibition and regenerate lost HCs. Findings from the proposed experiments could identify new therapeutic targets and lead to novel therapeutic approaches in the treatment of HC loss and eventual cure of deafness.

项目概要听觉支持细胞 (SC) 对于机械的正常发育、生存和功能至关重要感觉毛细胞（HC）及其支配神经元。 SC 的生物物理特性或功能缺陷导致听觉功能障碍和听力损失。尽管它们很重要，但控制的分子机制它们的发育和功能在很大程度上是未知的。我们提出的研究的一个主要目标是揭示指导听觉 SC 发育和功能的分子机制。我们最近发现 Notch 信号传导指导小鼠耳蜗 SC 发育。在这项拟议的研究中，我们将确定控制 SC 分化和存活的 Notch 配体和受体 (aim1) 描述了 Notch 信号传导及其靶标在 SC 引导的耳蜗神经支配中的潜在新作用，听觉功能（目标2）。我们提出的研究将加深我们对 Notch 信号传导机制的理解在分化 SC 中发挥作用，并为 SC 如何引导神经元神经支配提供新的见解以及控制耳蜗稳态。我们提出的研究的第二个主要目标是揭示控制哺乳动物SCs可塑性发育衰退的分子机制耳蜗。哺乳动物中的 HC 损失是永久性的，并且是人类耳聋的主要原因。在非哺乳动物脊椎动物的 SC 在动物的整个一生中都会再生丢失的 HC。在哺乳动物中，年轻通过抑制 Notch 信号或过度刺激 wnt，可以诱导未成熟的 SC 再生丢失的 HC 信号发送；然而，小鼠听觉 SC 对这种再生刺激的反应能力迅速下降产后第一周后。我们最近发现 RNA 结合蛋白 LIN28B 可以增强 HC 未成熟的耳蜗响应 Notch 信号而产生。在 Target3 中，我们将研究 LIN28B/let- 7轴修改了不成熟SC的再生响应，以及解决LIN28B是否重新成熟 SC 中的表达增强了它们响应 Notch 抑制和再生丢失的 HC 的能力。拟议实验的结果可以确定新的治疗靶点并产生新的治疗方法治疗 HC 损失和最终治愈耳聋的方法。