耳聋与耳蜗Cdh23基因突变有关。我们新发现的小鼠隐性突变，erlong（erl，突变基因；CDH23erl，突变蛋白），从正常听力到全聋间隔时间短，该模型适用于筛选和验证听力保护药物。据报道，一些耳聋患者具有的Cdh23突变与Cdh23erl/erl突变有类似的表型。听力损失与毛细胞的凋亡有关。但是Cdh23基因突变为何导致凋亡？本研究将测试这一假设：erl突变导致CDH23erl蛋白在内质网（ER）滞留，从而诱导未折叠蛋白反应（UPR），UPR信号可能诱导细胞凋亡。实验目的：测试假设（1）CDH23erl蛋白在ER内积累。（2）ER累积的CDH23erl蛋白引起UPR和内质网应激（ER stress），通过eIF2α-CHOP途径导致细胞凋亡。本项研究提供了一个新思路，将转变听觉毛细胞退化和再生的研究方向，表明突变蛋白诱发ER stress导致毛细胞丢失，并探索保护听力的治疗新靶点。

Age-related hearing loss (AHL) involves mutations of the cadherin 23 (Cdh23) gene in the cochlear hair cells of humans and mouse models. We have reported a novel recessive mutation erlong (erl is the symbol for the mutation; CDH23 is the symbol for the mutated protein) that is characterized by progressive hearing loss beginning from postnatal day 27 (P27). The short interval from normal hearing to deafness (P27–P90) and quick onset of hearing loss at high frequencies make this model ideal for evaluating otoprotective drugs. It is reported that some early-onset hearing loss patients had Cdh23 mutations with similar phenotypes as the Cdh23 mutants. Hearing loss was associated with the induction of hair cell apoptosis, but what is unknown is why the Cdh23 mutations induced apoptosis. This project aims to test the hypothesis that the erl mutations induce CDH23erl protein accumulated in the endoplasmic reticulum (ER) area, which then causes Unfolded Protein Response (UPR) and apoptosis. We will investigate UPR signaling in the pathogenesis of hearing loss. Specifically, this project aims to: (1) Test the hypothesis that the CDH23 protein is accumulated in the ER area. (2) Test the hypothesis that the ER accumulation of CDH23 protein in the ER causes UPR and ER stress that leads to apoptosis through the eIF2α–CHOP pathway. This proposal shifts the paradigm of research on auditory hair cell degeneration and regeneration by showing that a mutant protein induces ER stress, thereby leading to hair cell loss. These studies will provide new targets to explore protective therapies for age-related hearing loss.