ELMOD3在耳蜗毛细胞静纤毛发育和维持中的作用及致聋机制研究

耳聋是全球性重大公共卫生问题，开展遗传性耳聋致病机制研究是其防治关键。国外学者发现ELMOD3纯合突变导致重度语前聋；我们通过家系研究发现ELMOD3 c.512A>G杂合突变导致迟发性渐进性聋。我们构建的Elmod3敲除小鼠则出现渐进性聋和毛细胞静纤毛缺陷。静纤毛是毛细胞换能与听觉转导关键性结构。ELMODs家族成员作为ARF家族GTPase的GAPs与细胞骨架调控相关。我们推测：ELMOD3可能在毛细胞静纤毛发育和动态维持中起重要作用，因而突变致聋。本项目拟：①构建患者自体细胞来源的iPSCs建立疾病细胞模型，②构建携带患者突变、准确模拟人类病变的点突变KI小鼠模型，从细胞和动物水平探索ELMOD3基因功能及其突变的致病性。本项目有望深入理解ELMOD3这类GTPase的GAPs参与毛细胞静纤毛动态调控的分子基础和突变致聋机制，为相关耳聋疾病的诊断、预防、干预提供新的线索和依据。

Hearing loss is a major public health challenge globally, which is critical to investigate its pathogenesis to prevent. It has been reported that a homozygous mutation in ELMOD3 gene is associated with severe prelingual non-syndromic hearing loss. Our study also found that a heterozygous mutation (c.512A>G) in ELMOD3 causes progressive sensorineural hearing loss, suggesting the mutations in ELMOD3 gene lead to hereditary sensorineural hearing loss. In addition, we found that Elmod3 knock-out mice showed progressive hearing loss and dysmorphology of stereocilia in the sensory hair cells. Hair cell stereocilia are the key of electro-mechanical transduction. And ELMODs are single domain proteins that bind the activated conformation of a number of ARF family GTPases. So we predict that ELMOD3 may play an important role in the development and maintenance of stereocilia in hair cells, and its mutation can lead to hearing loss. In this project, we aim to ① establish the disease model from patient-specific induced pluripotent stem cells (iPSCs) with ELMODs mutation; ② construct the point mutation knock-in mice model with the same mutation as the patient carrying ELMOD3 mutation and accurately simulate human pathogenesis. Using these models, we could explore the function of ELMOD3 gene and its pathogenesis in the cellular and transgenic animal levels. In the end, conducting this project is expected to deeply understand the mechanism of these GAPs like ELMOD3 involving in the dynamic regulation of stereocilia in hair cells, and may provide new insights for the diagnosis, prevention and intervention of hearing loss associated diseases.