Pou4f3 enhancers in hearing loss treatment

数以百万计的人受到基因突变或基因突变引起的感音神经性听力损失的影响 环境刺激，目前还没有治疗感音神经性耳聋的方法。转录 POU4F3是感觉毛细胞分化、动态平衡和再生所必需的。在.期间 发展，POU4F3是Atoh1与许多毛细胞基因的增强子结合所必需的，以启动它们的 表达：听力发作后，由于一个等位基因的突变导致POU4F3的转录活性降低 毛细胞死亡和听力损失(DFNA15，常染色体显性遗传性非综合征性听力损失15，人类 在支持细胞中过表达POU4F3可刺激毛细胞命运转换。然而， Pou4f3基因的转录知之甚少，目前还没有可行的方法来调节Pou4f3 内源性等位基因的表达用于治疗DFNA15或再生毛细胞。在这个项目中，我们将 鉴定可能的Pou4f3增强子以研究转录调控机制 Pou4f3的表达，并利用这些可能的增强子刺激毛细胞中Pou4f3的表达 潜在的DFNA15治疗或支持细胞再生毛细胞的新策略。这项工作将 进一步了解调控毛细胞特异性基因表达的调控网络， 治疗DFNA15和与单倍体功能不全相关的其他形式的听力损失，以及 提供一种新的毛细胞再生策略，具有足够的灵活性以适应各种因素组合。

Millions of people are affected by sensorineural hearing loss caused by genetic mutations or environmental stimuli, and currently there is no curative treatment for sensorineural hearing loss. Transcription factor POU4F3 is essential for sensory hair cell differentiation, homeostasis and regeneration. During development, POU4F3 is required for ATOH1 to bind to enhancers of many hair cell genes to initiate their expression; after hearing onset, reduced transcription activity of POU4F3 due to mutations of one allele leads to hair cell death and hearing loss (DFNA15, autosomal dominant non-syndromic hearing loss 15, in human patients); and overexpression of POU4F3 in supporting cells stimulates hair cell fate conversion. However, the transcription of the Pou4f3 gene is poorly understood and there is no feasible method to regulate Pou4f3 expression from the endogenous allele to treat DFNA15 or to regenerate hair cells. In this project, we will characterize putative Pou4f3 enhancers to investigate the transcription regulatory mechanisms controlling Pou4f3 expression and utilize these putative enhancers to stimulate Pou4f3 expression in hair cells for a potential DFNA15 treatment or in supporting cells for a new strategy to regenerate hair cells. This work will further our understanding of the regulatory network governing hair cell specific gene expression, develop therapeutic treatments of DFNA15 and other forms of hearing loss associated with haploinsufficiency, and provide a new hair cell regeneration strategy with sufficient flexibility for a variety of factor combinations.