Spiral Ganglion Health: from Genomics to Gene Therapy

项目摘要 先天性听力损失影响到500名新生儿中的1名，使其成为人类最常见的感觉障碍。 听力损失的儿童有言语、语言和社会发展不良的风险，并有明显的负面影响 对生活质量的影响。治疗儿童重度至深度听力损失最有效的方法是人工耳蜗术。 植入。人工耳蜗术是人类最成功、应用最广泛的感觉假体 全球数十万人已经恢复了听力，植入人工耳蜗。而大多数人 在CI用户中，有很大一部分人在语音感知方面没有显著改善。有一个 迫切需要在人工耳蜗植入前确定有不良预后风险的个体，以便：(1)提供 准确的术前咨询，(2)量身定做的术后护理，以及(3)开发新的治疗策略 这些类型的听力损失。到目前为止，对CI言语感知结果的最好预测依赖于复杂的 与听力损失或术中耳蜗术相关的临床因素的统计建模 (ECOG)，这两种方法都不能在术前常规使用。越来越多的证据表明，特定的基因 对螺旋神经节神经元(SGN)健康产生负面影响的变异与更糟糕的情况有关 术后CI言语知觉结果。这项拨款提案的主要目标是更好地理解 遗传因素对儿童术后言语感知结果的影响。我们最近展示了 TMPRSS3基因的变异与较差的CI言语感知结果相关。虽然 TMPRSS3是遗传性听力损失最常见的原因之一，TMPRSS3蛋白的功能和 它导致听力损失的机制尚不清楚。TMPRSS3参与钙离子的表达- 内毛细胞的敏感钾通道。基因敲除的小鼠模型显示毛细胞迅速退化 在听证会开始后不久。然而，TMPRSS3中导致耳聋的突变值得注意的是导致NOT 不仅有重度至重度先天性听力损失(DFNB10)，而且还有较晚发病的舌后听力损失 (DFNB8)。此外，TMPRSS3的表达还包括毛细胞和SGN。我们假设 TMPRSS3在内毛细胞和SGN中都有作用。本项目的目的是：(1)检查 遗传学、ECoG和术后言语知觉评分之间的复杂相互作用 顺式，(2)通过开发新的迟发性小鼠模型来提高我们对TMPRSS3的理解 DFNB8听力损失，以及(3)开发一种治疗TMPRSS3听力损失的新基因疗法。的预期结果 这项研究将是：(1)儿童CI预后不良的遗传风险指数，(2)更好地理解 TMPRSS3在听力和听力损失中的作用；(3)一种新的TMPRSS3听力损失的基因治疗。这个 这项研究的结果将产生直接的临床影响，并为未来的基因治疗试验铺平道路 人类。

PROJECT ABSTRACT Congenital hearing loss affects 1 in 500 newborns, making it the most common sensory disorder in humans. Children with hearing loss are at risk for poor speech, language, and social development with noted negative effects on quality of life. The most effective treatment for severe-to-profound hearing loss in children is cochlear implantation. The cochlear implant (CI) is the most successful and widely used sensory prosthesis in humans and cochlear implantation has restored hearing to hundreds of thousands around the world. While the majority of CI users experience significant improvement in speech perception, a significant portion do not. There is a critical need to identify individuals at-risk for poor outcomes prior to cochlear implantation in order to: (1) provide accurate pre-operative counseling, (2) tailor post-operative care, and (3) develop new treatment strategies for these types of hearing loss. To date, the best predictors of CI speech perception outcomes rely on complex statistical modeling of clinical factors associated with hearing loss or intra-operative electrocochleography (ECoG), neither of which can be routinely used pre-operatively. There is increasing evidence that specific genetic variations that negatively affect the health of spiral ganglion neurons (SGNs) are associated with worse postoperative CI speech perception outcomes. The primary goal of this grant proposal is to better understand genetic contributors to postoperative speech perception outcomes in children. We recently showed that variations in the gene TMPRSS3 are associated with worse CI speech perception outcomes. Although TMPRSS3 is one of the most common causes of genetic hearing loss, the function of the TMPRSS3 protein and the mechanism by which it causes hearing loss are not known. TMPRSS3 is involved in expression of calcium- sensitive potassium channels in inner hair cells. A knock-out mouse model shows rapid hair cell degeneration soon after the onset of hearing. However, deafness-causing mutations in TMPRSS3 are notable for causing not only a severe-to-profound congenital hearing loss (DFNB10) but also a later onset post-lingual hearing loss (DFNB8). In addition, the expression of TMPRSS3 includes hair cells and also SGNs. We hypothesize that TMPRSS3 has functions in the inner hair cells as well as in the SGN. The aims of this project are to: (1) examine the complex interplay between genetics, ECoG, and post-operative speech perception scores in children with CIs, (2) improve our understanding of TMPRSS3 through development of a new mouse model for late onset DFNB8 hearing loss, and (3) develop a new gene therapy for TMPRSS3 hearing loss. The expected results of this study will be: (1) a genetic risk index for poor CI outcomes in children, (2) a better understanding of the function of TMPRSS3 in hearing and hearing loss, and (3) a novel gene therapy for TMPRSS3 hearing loss. The results of this study will have direct clinical impact as well as pave the way for future gene therapy trials in humans.