Regulation of auditory supporting cell differentiation and plasticity

听觉支持细胞分化和可塑性的调节

• 批准号: 9180695
• 负责人: Suzanne L Mansour
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180695
• 关键词: Adult; Affect; Age; Animals; Auditory; Back; Birds; Cell Differentiation process; Cells; Cochlea; Data; Development; Dominant-Negative Mutation; Embryo; Environmental Risk Factor; Epithelium; FGF10 gene; FGF8 gene; FGFR3 gene; Fibroblast Growth Factor; Fishes; Gene Deletion; Generations; Genetic; Genetic study; Goals; Hair Cells; Health Care Costs; Hearing; Heterozygote; Human; KRAS2 gene; Knockout Mice; Lateral; Lead; Learning; Ligands; MAP Kinase Gene; Mammals; Modeling; Mus; Mutation; Natural regeneration; Neonatal; Notch Signaling Pathway; Organ; Pathway interactions; Pattern; Perinatal; Phenotype; Pillar Cell; Population; Regulation; Residual state; Role; Sensorineural Hearing Loss; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Stem cells; Supporting Cell; Syndrome; System; Testing; Therapeutic; Time; Translations; Wild Type Mouse; design; fibroblast growth factor receptor 2b; hair cell regeneration; hearing impairment; in vivo; inner ear development; mouse model; mutant; notch protein; novel; postnatal; prospective; public health relevance; restoration; social; sound; spiral ganglion; tool; transcription factor

 DESCRIPTION (provided by applicant): Sensorineural hearing loss (SNHL) affects a large proportion of the population, generating significant social and health care costs. Many forms of SNHL feature damage to or loss of cochlear sensory hair cells (HCs), which do not regenerate in mammals. Strategies for hearing restoration are informed by studies of birds and fish, which, unlike mammals, spontaneously regenerate HCs from residual supporting cells (SCs). Notch signaling inhibition has emerged as a promising means of regenerating HCs. In mouse models, however, this approach is inefficient after embryonic stages, suggesting that manipulating additional developmental signals may be required. The FGF signaling system is a promising candidate because tight regulation of FGF signaling is critical to all stages of inner ear development, including HC and SC differentiation. We showed previously that mice with an FGFR3-activating mutation modeling Muenke syndrome, have dominant hearing loss associated with a SC fate switch of two Deiters' cells (DCs) to two pillar cells (PCs). The cell fate switch occurs perinatally and is associated with an expansion of FGF/RAS/MAPK signaling into the prospective DC region. Unexpectedly, hearing and SC fate are restored in these Fgfr3 mutants following genetic reduction of FGF10, a ligand that does not normally activate FGFR3. Remarkably, the SC fate switch still occurs in these rescued animals, but is resolved over time. This is associated with restoration of normal patterns of FGF signaling and shows that seemingly fully differentiated cochlear SCs can reversibly switch fates in an FGF-regulated manner. Although genetic data clearly implicate FGF8 as a ligand for FGFR3 in normal PC differentiation, the SC phenotype of Fgf8 otic conditional knockout mice is weaker than that of the Fgfr3 null mice, suggesting that additional Fgfs are involved. Furthermore, the rescue of Muenke syndrome model phenotypes by Fgf10 heterozygosity begs the question of the normal role of cochlear Fgf10 in the perinatal period. Fgf3 is also expressed near developing SCs, but its role in their development is unknown. These data collectively lead to the hypothesis that FGF10 signals are required for development of Fgfr3P244R/+ phenotypes and that Fgf10 and/or Fgf3 are required together with Fgf8 for normal PC differentiation. This will be tested by temporal and spatial regulation FGF signaling in Muenke syndrome model and wild type mice (Aim 1). Our finding of FGF-regulated supporting cell plasticity and the observations by others that DCs express Fgfr3 into adulthood and that Notch inhibition can promote HC regeneration from SC progenitors, suggest the hypothesis that normal perinatal DCs can be transformed into PCs by forced activation of the RAS/MAPK pathway and that Notch inhibition induced in the context of FGF/RAS/MAPK activation will promote HC differentiation. This will be tested using spatial and temporal modulation of the two signaling pathways in vivo (Aim 2). Completion of the Aims will impact the development of strategies that employ developmental signals for hearing restoration.

 描述（由申请人提供）：感音神经性听力损失（SNHL）影响大部分人口，产生显著的社会和医疗保健成本。许多形式的SNHL的特征是耳蜗感觉毛细胞（HC）的损伤或损失，这些细胞在哺乳动物中不能再生。听力恢复的策略是通过对鸟类和鱼类的研究得知的，与哺乳动物不同，鸟类和鱼类会从残留的支持细胞（SC）中自发再生HC。Notch信号传导抑制已经成为再生HC的有希望的手段。然而，在小鼠模型中，这种方法在胚胎阶段后效率低下，这表明可能需要操纵额外的发育信号。FGF信号传导系统是一个有前途的候选者，因为FGF信号传导的严格调节对于内耳发育的所有阶段（包括HC和SC分化）都是至关重要的。我们先前表明，具有FGFR 3激活突变模型Muenke综合征的小鼠具有与两个Deiters细胞（DC）到两个柱细胞（PC）的SC命运转换相关的显性听力损失。细胞命运转换发生在围产期，并与FGF/RAS/MAPK信号传导扩展到预期的DC区域相关。出乎意料的是，在FGF 10（一种通常不激活FGFR 3的配体）的遗传减少后，这些FGFR 3突变体中的听力和SC命运得以恢复。值得注意的是，SC命运转换仍然发生在这些获救的动物中，但随着时间的推移而解决。这与FGF信号传导的正常模式的恢复有关，并且表明看似完全分化的耳蜗SC可以以FGF调节的方式可逆地切换命运。虽然遗传数据清楚地表明FGF 8作为FGFR 3在正常PC分化中的配体，但Fgf 8耳条件性敲除小鼠的SC表型比Fgfr 3缺失小鼠的SC表型弱，表明涉及额外的Fgf。此外，救援的Muenke综合征模型表型的Fgf 10杂合性回避的问题，耳蜗Fgf 10在围产期的正常作用。Fgf 3也在发育中的SC附近表达，但其在其发育中的作用尚不清楚。这些数据共同导致了这样的假设，即FGF 10信号是Fgfr 3 P244 R/+表型发展所需的，并且Fgf 10和/或Fgf 3与Fgf 8一起是正常PC分化所需的。这将通过在Muenke综合征模型和野生型小鼠中的时间和空间调节FGF信号传导来测试（Aim 1）。我们发现FGF调节的支持细胞可塑性和其他人的观察，DC表达Fgfr 3到成年期，Notch抑制可以促进HC从SC祖细胞再生，这表明正常围产期DC可以通过RAS/MAPK途径的强制激活转化为PC，并且在FGF/RAS/MAPK激活的背景下诱导的Notch抑制将促进HC分化。这将在体内使用两种信号传导途径的空间和时间调制进行测试（目的2）。目标的完成将影响采用发育信号进行听力恢复的策略的制定。