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)：感觉神经性听力损失(SNHL)影响了很大一部分人口，产生了巨大的社会和医疗成本。许多形式的SNHL的特征是耳蜗感觉毛细胞(HC)的损伤或丢失，而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出的，与哺乳动物不同，鸟类和鱼类会自发地从残留的支持细胞(SCs)中再生HC。Notch信号抑制已经成为一种很有前途的再生HCS的方法。然而，在小鼠模型中，这种方法在胚胎阶段之后效率低下，这表明可能需要操纵额外的发育信号。成纤维细胞生长因子信号系统是一个很有前景的候选系统，因为对成纤维细胞生长因子信号的严格调控对内耳发育的所有阶段都是至关重要的，包括内耳发育的HC和SC分化。我们先前证明，带有模拟Muenke综合征的FGFR3激活突变的小鼠，具有与两个Deiters细胞(DC)到两个支柱细胞(PC)的SC命运切换相关的显性听力损失。细胞命运转换发生在围产期，并与成纤维细胞生长因子/RAS/MAPK信号扩展到预期的DC区域有关。出人意料的是，在FGF10(一种正常情况下不激活FGFR3的配体)的遗传减少后，这些FGFR3突变体恢复了听力和SC的命运。值得注意的是，SC命运的改变仍然发生在这些获救的动物身上，但随着时间的推移会得到解决。这与恢复成纤维细胞生长因子信号的正常模式有关，并表明看似完全分化的耳蜗干细胞可以通过成纤维细胞生长因子调节的方式可逆地改变命运。尽管遗传数据清楚地表明FGF8在正常的PC分化中是FGFR3的配体，但Fgf8条件基因敲除小鼠的SC表型弱于FGFR3缺失小鼠，这表明额外的FGFs参与了PC的分化。此外，Fgf10杂合性挽救Muenke综合征模型表型提出了耳蜗Fgf10在围产期的正常作用的问题。Fgf3在发育中的干细胞附近也有表达，但其在干细胞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FGF10信号是Fgfr3P244R/+表型发育所必需的，Fgf10和/或Fgf3与Fgf8一起是正常PC分化所必需的。这将通过在Muenke综合征模型和野生型小鼠(目标1)中的时间和空间调节的成纤维细胞生长因子信号来验证。我们的发现和其他人的观察到DC在成年期表达FGFR3，并且Notch抑制可以促进SC祖细胞再生HC，这提示我们的假设是，正常围产期DC可以通过强制激活Ras/MAPK通路而转化为PC，而在FGF/Ras/MAPK激活的背景下诱导的Notch抑制将促进HC的分化。这将通过在体内对两个信号通路进行空间和时间调制来测试(目标2)。这些目标的完成将影响利用发育信号恢复听力的策略的发展。