Outer and Inner Hair Cell Development

外毛细胞和内毛细胞发育

基本信息

批准号：
10194450
负责人：
Jaime Garcia-Anoveros
金额：
$ 49.08万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10194450
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

项目摘要

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.

项目概要耳蜗含有两种类型的机械感觉受体细胞：内毛细胞 (IHC) 和外毛细胞 (OHC)，它们在听力中发挥着非常不同但至关重要的作用。耳蜗毛细胞在胚胎发生过程中产生，但如何产生它们具体分化为 IHC 或 OHC 仍不清楚。我们发现了一个推测的转录因子在小鼠胚胎发生过程中，(INSM1) 在早期 OHC 中表达，但在 IHC 中不表达。 Insm1是第一个基因发现在新生、早期分化的 OHC（但不是 IHC）中独特表达。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 INSM1 的作用是在 OHC 分化早期调节（激活或抑制）其他基因，并将识别这些目标基因。最后，我们将利用独特的报告系 (Insm1GFP::Cre) 选择性地标记来自他们开始细胞分选并识别胚胎 OHC 中独特或优先表达的基因和蛋白质或 IHC。然后，我们将对其中一些基因进行功能测试，以确定其在 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 OHC 和 IHC 如何区分的方法他们独特的特点。这些知识对于恢复听力的疗法的开发至关重要毛细胞死亡，因为这需要特定的 OHC、IHC 或两者替代。