Determining the Molecular Landscape Necessary for Hair Cell Differentiation

项目总结 内耳内的毛细胞将声音刺激转化为电脉冲，然后传输 通过传入神经元传递到大脑。毛细胞缺失或失聪的个体听力丧失 失聪的听力丧失了。毛细胞修复的主要障碍之一是毛细胞死亡后， Corti的感觉器官最终被扁平的立方体上皮所取代。PST研究表明 这些细胞不能接受向毛细胞的跨分化。因此，至关重要的是要定义 形成感觉前上皮并提供潜在基因调控的分子 支持参与毛细胞分化的转录因子的网络。为此，我们有 确定早期听觉GATA3的表达对于感觉规范和毛细胞是必要的 差异化。此外，在取代GATA3的扁平上皮中，GATA3的水平严重降低 毛细胞丢失后的Corti器官。GATA3在发育中的感觉器官中继续表达 然而，随着上皮细胞和毛细胞的分化，它们后来在这些事件中的表达并没有 被刻画出来了。基于这些观察，我们假设持续表达的 在前感的发育和分化过程中，GATA3的精确水平是持续需要的 上皮细胞和毛细胞。我们将通过调查1)在这些过程中GATA3的丢失来检验这一假设 时间点及其对指定细胞采用感觉命运和毛细胞采用感觉命运的影响 正确区分，2)GATA3在这些时间点的表达增加，以及如何增加 水平影响这些细胞类型，以及3)GATA3的表达是否能将扁平上皮改变为更具感觉的 就像州政府一样。最后，本研究将为后续的研究奠定基础和提供初步数据 R01。

PROJECT SUMMARY Hair cells within the inner ear transform sound stimuli into electrical impulses to then be transmitted to the brain by afferent neurons. Hearing is lost in individuals where hair cells are absent or dysfunctional hearing is lost. One of the major hurdles in hair cell restoration is that after hair cell death, the sensory organ of Corti is eventually replaced by a flat cuboidal epithelium. Pst research has shown that these cells are not receptive to transdifferentation into hair cells. Therefore, it is critical to define the molecules that give rise to the prosensory epithelia and provide the underlying gene regulatory network that support transcription factors involved in hair cell differentiation. Towards this end, we have identified early otic Gata3 expression is necessary for prosensory specification and hair cell differentiation. In addition, the level of Gata3 is severely reduced in the flat epithelium that replaces the organ of Corti after hair cell loss. Gata3 continues to be expressed in the developing prosensory epithelia and hair cells as they differentiate, however, its later expression during these events has not been characterized. Based upon these observations, we hypothesize that the continued expression of precise levels of Gata3 are continually needed during the development and differentiation of prosensory epithelia and hair cells. We will test this hypothesis by investigating 1) the loss of Gata3 during these time points and its effect on the specification of cells to adopt a prosensory fate and on hair cells to correctly differentiate, 2) increased expression of Gata3 during these time points and how this increased level effects these cell types, and 3) if Gata3 expression can alter the flat epithelium into a more sensory like state. Finally, this research will lay the foundation and provide preliminary data for a subsequent R01.