The role of supporting cell de-differentiation in cochlear hair cell regeneration

支持细胞去分化在耳蜗毛细胞再生中的作用

基本信息

  • 批准号:
    10606664
  • 负责人:
  • 金额:
    $ 4.68万
  • 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:
    2022-09-01 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Cochlear Hair Cell (HC) loss is a leading cause of noise-induced and age-related hearing loss worldwide. Regeneration of HCs in response to damage has been observed in nonmammalian species, such as birds and fish, but is not observed in the mature mammalian cochlea. Although Supporting Cells (SCs), a diverse population of cells offering metabolic and structural support to hair cells, show the capacity to produce hair cells in neonatal mice, this plasticity is lost by postnatal day 5. Previous work from our lab has identified the de-differentiation of SCs into a more progenitor-like state as a key component of the HC regenerative process, as hair cells and supporting cells arise from a common progenitor pool during cochlear development. Supporting cell de-differentiation, the downregulation in expression of supporting cell-specific genes and upregulation in expression of, allows the progenitor-like cells to respond to HC fate-inducing cues. Preliminary studies have identified members of the NFI and ZBTB families of transcription factors as potential regulators of SC identity, maintaining SCs in a terminally differentiated state and preventing endogenous reprogramming. The NFI factors have previously been studies in the context of retinal regeneration, where they have been shown to regulate retinal Müller glial cell differentiation. Additionally, disruption of NFI factor function has been shown to promote conversion of Müller glia into retinal neurons. Zbtb20 has been implicated in astrocytogenesis, and has been linked to Primrose syndrome, a rare developmental disorder which is known to cause hearing loss. The overarching hypothesis of this grant proposal is that Nfia/b/c/x and Zbtb20 are crucial in maintaining SC identity, and that loss of one or more of these factors will enable SC reprogramming and HC regeneration in stage P5 mouse tissue. This hypothesis will be tested using in vitro cochlear organoid culture derived from stage P2 and P5 murine cochlear sensory epithelia. Additionally, the function of Zbtb20 will be studied in vivo and in a HC damage model. I will use RT-qPCR, fluorescence imaging of a HC reporter line, immunolabeling, EdU pulse experiments, and scRNA-sequencing in Aim 1 to determine if gain of function of NFIA/B/C/X or ZBTB20 inhibits cochlear SC reprogramming and SC-based HC formation at stage P2 in vitro and in Aim 2 to determine if loss of function of NFIA/B/C/X or ZBTB20 enhances cochlear SC plasticity and SC-based HC formation at stage P5 in vitro. In Aim 3, I will use immunolabeling, RT-qPCR, EdU pulse experiments, and a HC damage model to define the role of Zbtb20 in maintaining SCs in a terminally differentiated state. These studies will expand our knowledge of SC identity maintenance and the HC regenerative process and will aid future translational research using regenerative therapies to treat hearing loss in humans.
项目总结 耳蜗毛细胞(HC)丢失是噪声性和老年性听力损失的主要原因 全世界。在非哺乳动物物种中观察到了对损伤做出反应的HCS的再生,如 与鸟类和鱼类一样,但在成熟的哺乳动物耳蜗中没有观察到。虽然支持细胞(SC),但 不同种类的细胞为毛细胞提供代谢和结构支持,显示出产生 新生小鼠的毛细胞,这种可塑性在出生后第5天就会消失。我们实验室之前的工作已经确定 作为HC再生关键成分的干细胞去分化为更多的祖细胞样状态 这个过程,因为毛细胞和支持细胞产生自一个共同的祖细胞池在耳蜗发育过程中。 支持细胞去分化,下调支持细胞特异性基因的表达和 表达上调,允许祖细胞样细胞对HC命运诱导信号做出反应。 初步研究已确定NFI和ZBTB转录因子家族成员为 SC身份的潜在调节者,保持SC处于终末分化状态并防止 内源性重新编程。NFI因子以前是在视网膜的背景下进行研究的 再生,在那里它们已被证明调节视网膜Müler神经胶质细胞的分化。另外, 研究表明,破坏NFI因子的功能可以促进Müller神经胶质细胞向视网膜神经元的转化。 Zbtb20与星形细胞形成有关,并与一种罕见的报春花综合征有关。 已知会导致听力损失的发育障碍。 这项赠款提案的首要假设是,Nfia/b/c/x和Zbtb20在 维护SC身份,失去这些因素中的一个或多个将使SC重新编程 和P5期小鼠组织中的HC再生。这一假说将通过体外耳蜗术进行验证。 器官培养来源于P2和P5期的小鼠耳蜗感觉上皮。此外,它的功能 Zbtb20将在体内和HC损伤模型中进行研究。我将使用RT-qPCR,一种HC的荧光成像 报告线,免疫标记,EDU脉冲实验,和目标1中的scRNA测序,以确定是否获得 NFIA/B/C/X或ZBTB20功能抑制耳蜗期SC重编程和基于SC的HC形成 P2在体外和目的2中确定NFIA/B/C/X或ZBTB20功能丧失是否增强耳蜗SC 体外可塑性和基于SC的HC在P5期的形成。在目标3中,我将使用免疫标记、RT-qPCR、EDU 脉冲实验,和HC损伤模型,以定义Zbtb20在维持终末SCs中的作用 分化状态。这些研究将扩大我们对SC身份维护和HC的了解 再生过程,并将有助于未来使用再生疗法治疗听力的翻译研究 人类的损失。

项目成果

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