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: 9028525
• 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/9028525
• 关键词: Adult; Affect; Age; Animals; Auditory; Back; Birds; Cell Differentiation process; Cells; Cochlea; Cues; 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; Health Care Costs; Hearing; Heterozygote; Human; KRAS2 gene; Knockout Mice; Labyrinth; Lateral; Lead; Learning; Ligands; MAP Kinase Gene; Mammals; Modeling; Mus; Mutation; Natural regeneration; Neonatal; Organ; Pathway interactions; Pattern; Perinatal; Phenotype; Pillar Cell; Population; Psyche structure; Regulation; Residual state; Role; Sensorineural Hearing Loss; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Staging; Supporting Cell; Syndrome; System; Testing; Therapeutic; Time; Translations; Wild Type Mouse; design; ear development; fibroblast growth factor receptor 2b; hair cell regeneration; hearing impairment; in vivo; mouse model; mutant; notch protein; novel; postnatal; progenitor; prospective; 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) 影响很大一部分人口，产生巨大的社会和医疗保健费用。许多形式的 SNHL 都以耳蜗感觉毛细胞 (HC) 受损或丧失为特征，而哺乳动物的耳蜗感觉毛细胞无法再生。听力恢复策略是根据对鸟类和鱼类的研究得出的，与哺乳动物不同，鸟类和鱼类能够从残留的支持细胞 (SC) 中自发再生 HC。 Notch 信号传导抑制已成为一种有前景的 HC 再生方法。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）至关重要。我们之前表明，具有 FGFR3 激活突变的 Muenke 综合征小鼠具有显性听力损失，这与两个 Deiters 细胞 (DC) 到两个支柱细胞 (PC) 的 SC 命运转换有关。细胞命运转换发生在围产期，并与 FGF/RAS/MAPK 信号向预期 DC 区域的扩展相关。出乎意料的是，在 FGF10（一种通常不激活 FGFR3 的配体）基因减少后，这些 Fgfr3 突变体的听力和 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身上，但随着时间的推移会得到解决。这与 FGF 信号传导正常模式的恢复有关，并表明看似完全分化的耳蜗 SC 可以以 FGF 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 PC 分化中作为 FGFR3 的配体，但 Fgf8 耳条件敲除小鼠的 SC 表型比 Fgfr3 缺失小鼠的 SC 表型弱，表明额外的 Fgf 也参与其中。此外，Fgf10 杂合性对 Muenke 综合征模型表型的拯救引发了耳蜗 Fgf10 在围产期正常作用的问题。 Fgf3 也在发育中的 SC 附近表达，但其在 SC 发育中的作用尚不清楚。这些数据共同得出这样的假设：FGF10 信号是 Fgfr3P244R/+ 表型发育所必需的，并且 Fgf10 和/或 Fgf3 与 Fgf8 一起是正常 PC 分化所必需的。这将通过 Muenke 综合征模型和野生型小鼠的时间和空间调节 FGF 信号传导进行测试（目标 1）。我们对 FGF 调节的支持细胞可塑性的发现以及其他人对 DC 表达 Fgfr3 到成年期以及 Notch 抑制可以促进 SC 祖细胞的 HC 再生的观察结果表明，正常围产期 DC 可以通过强制激活 RAS/MAPK 途径转化为 PC，并且在 FGF/RAS/MAPK 激活背景下诱导的 Notch 抑制将促进 HC 分化。这将通过体内两条信号通路的空间和时间调制进行测试（目标 2）。目标的完成将影响利用发育信号恢复听力的策略的制定。