The function of Hes and Hey genes in maintaining a supporting cell state

描述（由申请人提供）：本提案的目的是研究he和Hey家族的转录抑制因子在支持细胞发育中的功能及其在抑制毛细胞再生中的潜在参与。哺乳动物失去的毛细胞不能再生，而毛细胞的丧失是人类耳聋的主要原因。相比之下，鸟类的支持细胞可以作为毛细胞祖细胞，能够再生失去的毛细胞。分化为毛细胞还是支持细胞是由Notch信号控制的。在内耳中，Notch信号被认为是由Hes1和Hes5两种转录抑制因子介导的，这两种转录抑制因子属于hairy and enhancer of split （HES）家族。我们最近发现HES相关的Hey基因（Hey1, Hey2, HeyL）在分化支持细胞中与Hes1和Hes5共表达。在Specific Aim 1中，我们将讨论he和Hey基因是否协同作用以维持支持细胞的特定状态。我们将根据它们的表达模式组合生成Hey Hes突变小鼠，并分析单突变和双突变小鼠支持细胞向毛细胞反分化的程度。在特异性目的2中，我们打算确定在受损的Corti器官中，Hey和Hes基因的持续表达是否会阻碍毛细胞再生。我们建议分析he和Hey突变体支持细胞在原代细胞培养中是否具有增强的毛细胞生成能力。进一步，我们建议使用器官培养来测试he或Hey功能的丧失是否足以诱导受损耳蜗的毛细胞再生。在这项拨款申请中，我们想要研究he和Hey基因家族的转录抑制因子在抑制毛细胞再生中的作用。内耳感觉毛细胞的丢失是耳聋和平衡障碍的主要原因。了解阻止哺乳动物毛细胞再生的分子机制对于开发成功的毛细胞替代疗法至关重要。

DESCRIPTION (provided by applicant): The Aim of this proposal is to study the function of transcriptional repressor of the Hes and Hey family in supporting cell development and their potential involvement in repressing hair cell regeneration. Mammals do not regenerate lost hair cells and hair cell loss is a leading cause for deafness in humans. In contrast, supporting cells in birds can function as hair cell progenitors and are capable to regenerate lost hair cells. The choice whether to differentiate into a hair cell or a supporting cell, is controlled by Notch signaling. In the inner ear Notch signaling is believed to be mediated by Hes1 and Hes5, two transcriptional repressors belonging to hairy and enhancer of split (HES) family. We recently discovered that HES related Hey genes (Hey1, Hey2, HeyL) are co-expressed with Hes1 and Hes5 in differentiating supporting cells. In Specific Aim 1 we will address the question if the Hes and Hey genes function synergistically to maintain a supporting cells specific state. We will generate based on their expression pattern combinations of Hey Hes mutant mice and analyze the extent of supporting cell to hair cell trans-differentiation in the single mutant and double mutant mice. In Specific Aim 2 we propose to determine if the persistence of Hey and Hes gene expression in the damaged organ of Corti blocks hair cell regeneration. We propose to analyze if Hes and Hey mutant supporting cells have an enhanced capacity to generate hair cells in primary cell culture. Further we propose to test if loss of Hes or Hey function is sufficient to induce hair cell regeneration in the damaged cochlear using organ culture. In this grant proposal, we want to investigate the role of transcriptional repressors of the Hes and Hey gene family in inhibiting hair cell regeneration. Sensory hair cell loss in the inner ear is a leading cause of deafness and balance disorders. Understanding the molecular mechanisms preventing hair cell regeneration in mammals is crucial for developing successful hair cell replacement therapies.