Pou4f3 enhancers in hearing loss treatment

数以百万计的人受到由基因突变引起的感音神经性听力损失的影响， 感音神经性听力损失通常是由环境刺激引起的，并且目前没有针对感音神经性听力损失的治愈性治疗。转录 POU 4F 3因子是感觉毛细胞分化、稳态和再生所必需的。期间 POU 4F 3是ATOH 1与许多毛细胞基因的增强子结合所必需的， 表达;听力发作后，由于一个等位基因突变导致POU 4F 3转录活性降低， 毛细胞死亡和听力损失（DFNA 15，常染色体显性遗传性非综合征性听力损失15，在人类 患者）;并且支持细胞中POU 4F 3的过表达刺激毛细胞命运转换。但 对Pou 4f 3基因的转录了解甚少，并且没有可行的方法来调节Pou 4f 3 在一些实施方案中，所述方法包括从内源等位基因表达来治疗DFNA 15或再生毛细胞。在这个项目中，我们将 表征推定的Pou 4f 3增强子，以研究控制转录的转录调节机制。 Pou 4f 3的表达，并利用这些推定的增强子刺激毛细胞中Pou 4f 3的表达， 潜在的DFNA 15治疗或支持细胞再生毛细胞的新策略。这项工作将 进一步了解毛细胞特异性基因表达的调控网络， DFNA 15和与单倍不足相关的其他形式的听力损失的治疗性治疗，以及 提供了一种新的毛细胞再生策略，其对于多种因子组合具有足够的灵活性。

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.