Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance

项目总结 感觉毛细胞(HCS)及其神经细胞。干细胞生物物理性质或功能的缺陷 导致听力障碍和听力损失。尽管它们很重要，但控制它们的分子机制 它们的发展和功能在很大程度上是未知的。我们提议的研究的一个主要目标是揭示 引导听觉干细胞发育和功能的分子机制。我们最近发现了 Notch信号指导小鼠耳蜗中SC的发育。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(S)和受体(S)(AIM1) 表征Notch信号及其靶点在SC引导的耳蜗神经支配和传导中的潜在新作用 听觉功能(AIM2)。我们提出的研究将促进我们对Notch信号如何 也为干细胞如何引导神经元神经支配提供了新的见解 我们建议的研究的第二个主要目标是揭示 哺乳动物干细胞可塑性发育下降的分子机制 耳蜗骨。哺乳动物体内的HC丢失是永久性的，也是导致人类耳聋的主要原因。在非- 哺乳动物脊椎动物的干细胞在动物的一生中再生丢失的HCs。在哺乳动物中，幼崽 然而，小鼠听觉SC对这种再生刺激的反应能力迅速下降 在出生后第一周之后。我们最近发现RNA结合蛋白Lin28b能增强HC Notch信号在未成熟的耳蜗组织中的产生。在目标3中，我们将调查LIN28B/LET如何- 7轴改变未成熟干细胞的再生反应，并解决Lin28b是否重新启动 在成熟干细胞中的表达增强了它们对Notch抑制的反应能力和再生丢失的HCs的能力。 拟议实验的发现可能会确定新的治疗靶点，并导致新的治疗方法 耳聋的治疗和最终治愈的方法。

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.