The Role of Sox2 in the Formation and Maintenance of Sensory Regions in Inner Ear Development

Sox2 在内耳发育中感觉区域的形成和维持中的作用

基本信息

  • 批准号:
    10553122
  • 负责人:
  • 金额:
    $ 4.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Understanding the development of the inner ear is extremely important for human health. Inner ear sensory organs contain mechanosensitive hair cells required for hearing and balance. Hair cells are killed by damage from loud noises and certain ototoxic drugs. The mammalian inner ear has minimal regenerative capacity for forming new hair cells, so when damage occurs it can cause permanent hearing loss. Beyond damage, there are a variety of possible mechanisms resulting in reduced hearing, balance issues, or deafness occurring in the global population. Understanding how the inner ear develops can provide insights into the failure of hair cell regeneration in mammals and may reveal strategies to restore hearing in humans. The Notch signaling pathway and specifically the pluripotency factor Sox2 play important roles in inner ear development. Sox2, as a Notch downstream target, is expressed broadly during early inner ear development. However, as the ear continues to develop, Sox2 expression becomes restricted to prosensory domains, regions of the inner ear that will later develop into auditory or vestibular sensory organs. The rest of the embryonic inner ear will form nonsensory structures such as the semicircular canals. Data from our lab suggests that Sox2 expression is present in both prosensory and nonsensory progenitors during early inner ear development but become restricted to prosensory regions over time. The aim of this study is to understand the role of Sox2 during early inner ear development. To test our hypothesis that the developmental potential of Sox2-expressing progenitor cells changes over time, we will use a cell lineage tracing method to test whether an individual Sox2- expressing cell is capable of generating prosensory or nonsensory cells, or both. In parallel, we will test whether transcriptional targets of Sox2 change over time during ear development. Using a Sox2-RFP reporter mouse line developed in our lab, we will isolate Sox2-expressing cells and identify the targets of Sox2 by a chromatin immunoprecipitation-based assay (CUT&RUN). We will combine this with transcriptomic studies (RNA-seq) to analyze how Sox2 binding is changing and affecting the transcriptional output at early and late time points of inner ear development. Combining the results of methods like CUT&RUN and RNAseq will help us understand how Sox2 differentially targets genes over time, as well as how this affects the overall transcriptome of the developing otocyst. Our work will reveal the functional shift of a key regulator of inner ear development, gain a more specific understanding of how cells specify to become hair cells through development, and identify new strategies to target cells for hair cell regeneration.
项目总结 了解内耳的发育对人类健康极其重要。内耳感觉 器官中含有听力和平衡所需的机械敏感毛细胞。毛细胞因损伤而死亡 由于巨大的噪音和某些耳毒性药物。哺乳动物内耳的再生能力最低 形成新的毛细胞,所以当损伤发生时,它可能会导致永久性听力损失。除了破坏,还有 是否有多种可能的机制导致听力下降、平衡问题或耳聋发生在 全球人口。了解内耳是如何发育的,有助于深入了解头发脱落的原因。 哺乳动物中的细胞再生,并可能揭示恢复人类听力的策略。Notch信令 途径,特别是多能因子Sox2在内耳发育中起着重要作用。SOX2,作为一个 Notch下游靶基因,在内耳发育早期广泛表达。然而,作为耳朵, 继续发展,SOX2的表达变得受限于前感觉区,内耳的区域 以后会发育成听觉或前庭感觉器官。胚胎内耳的其余部分将形成 非感觉性结构,如半规管。我们实验室的数据表明,Sox2的表达是 在内耳发育的早期存在于感觉前体细胞和无感觉前体细胞中,但 随着时间的推移被限制在前感觉区。这项研究的目的是了解Sox2在早期的作用 内耳发育。来验证我们的假设,即表达Sox2的祖细胞的发育潜力 细胞随时间变化,我们将使用细胞谱系追踪方法来测试单个Sox2- 表达细胞能够产生感觉或无感觉细胞,或两者兼而有之。同时,我们将测试 在耳朵发育过程中,Sox2的转录靶标是否会随着时间的推移而变化。使用Sox2-RFP记者 在本实验室建立的小鼠系中,我们将分离表达Sox2的细胞,并通过 染色质免疫沉淀法(CUT&RUN)。我们将把这一点与转录研究结合起来 (RNA-seq)来分析Sox2结合是如何改变和影响早期和后期的转录输出的 内耳发育的时间点。将Cut&Run和RNAseq等方法的结果结合起来会有所帮助 我们了解Sox2如何随着时间的推移而以不同的基因为靶标,以及这如何影响整体 发育中的耳囊转录组。我们的工作将揭示内耳一个关键调节因子的功能变化 发展,更具体地了解细胞是如何通过 开发,并确定以毛细胞再生为靶细胞的新策略。

项目成果

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