Outer and Inner Hair Cell Development

外毛细胞和内毛细胞发育

• 批准号: 10418970
• 负责人: Jaime Garcia-Anoveros
• 金额: $ 5.34万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418970
• 关键词: Ablation; Adult; Affect; Afferent Neurons; Alleles; Apical; Appearance; Birth; C2H2 Zinc Finger; Cell Death; Cell Differentiation process; Cells; Cessation of life; Cochlea; Development; Efferent Neurons; Embryo; Embryonic Development; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Hair Cells; Hearing; Immunohistochemistry; In Situ Hybridization; Inner Hair Cells; Knowledge; Label; LoxP-flanked allele; Mammals; Messenger RNA; Mus; Natural regeneration; Noise; Outer Hair Cells; Play; Post-Transcriptional Regulation; Property; Proteins; Proteome; Proteomics; RNA Splicing; Receptor Cell; Reporter; Reporter Genes; Reporting; Resolution; Role; Shotguns; Supporting Cell; Technology; Testing; Therapeutic; Time; Transcript; Transcriptional Regulation; Translations; age related; cell type; deafness; differential expression; hearing impairment; hearing restoration; normal hearing; paralogous gene; prevent; progenitor; ranpirnase; receptor; regenerative approach; stem cells; therapy development; transcription factor; transcriptome; transcriptome sequencing

Project Summary The cochlea contains two types of mechanosensory receptor cells, inner (IHC) and outer (OHC) hair cells, which play very different, but critical, roles in hearing. Cochlear hair cells arise during embryogenesis, but how they specifically differentiate into IHCs or OHCs remains unknown. We found a presumed transcription factor (INSM1) expressed in incipient OHCs, but not in IHCs, during mouse embryogenesis. Insm1 is the first gene found to be uniquely expressed in nascent, early differentiating OHCs (but not IHCs). We find that ablating Insm1 affects OHCs and will elucidate its role in OHC differentiation. We hypothesize that INSM1 acts by regulating (either activating or repressing) other genes early in OHC differentiation and will identify these target genes. Finally, we will take advantage of a unique reporter line (Insm1GFP::Cre) that selectively labels OHCs from their onset to cell sort and identify genes and proteins uniquely or preferentially expressed in embryonic OHCs or IHCs. We will then functionally test some of these genes for roles in OHC- and IHC-specific development. These approaches offer for the first time the means to elucidate how cochlear OHCs and IHCs differentiate their unique features. This knowledge will be critical for the development of therapies to restore hearing due to hair cell death, as this will require the specific replacement of OHCs, IHCs or both.

项目摘要 耳蜗包含两种类型的机械感觉受体细胞，内毛细胞（IHC）和外毛细胞（OHC）， 它们在听觉中扮演着非常不同但至关重要的角色。耳蜗毛细胞在胚胎发育过程中出现，但如何 它们具体区分为IHC还是OHC仍然未知。我们发现了一个假定的转录因子 在小鼠胚胎发生过程中，INSM 1在早期OHC中表达，但在IHC中不表达。Insm1是第一个 发现在新生的、早期分化的OHC（但不是IHC）中独特地表达。我们发现消融 Insm1影响OHC，并将阐明其在OHC分化中的作用。我们假设INSM 1通过以下方式起作用： 在OHC分化早期调节（激活或抑制）其他基因，并将识别这些靶点 基因.最后，我们将利用一个独特的报告细胞系（Insm1GFP：：Cre），它选择性地标记来自 他们的发病细胞分类和鉴定基因和蛋白质独特或优先表达在胚胎外毛细胞 或IHC。然后，我们将在功能上测试这些基因中的一些在OHC和IHC特异性发育中的作用。 这些方法首次提供了阐明耳蜗外毛细胞和内毛细胞如何区分的手段 他们的独特之处。这些知识对于开发恢复听力的疗法至关重要， 毛细胞死亡，因为这将需要特定的替代OHC，IHC或两者。