CDH23和PCDH15的钙离子依赖性相互作用形成了毛细胞的顶连接, 调控耳蜗Corti 器的MET通道。在人类CDH23突变所致的听力障碍中，以错义突变所引起的DFNB12最为常见,其发病机理尚不清楚。我们建立了独特的DFNB12小鼠（erl）模型，基因突变引起CDH23氨基酸的替换(S70P)，导致CDH23二级结构的改变,小鼠表现为出生后27到90天渐进性的听力减退，期间毛细胞缺失从耳蜗底回向顶回蔓延，这种演变过程为erl小鼠耳聋的机理研究和干预提供了良机。我们认为erl突变所导致的毛细胞顶连接的结构与功能的改变是小鼠听力减退的主要原因。本课题拟体外表达erl小鼠的CDH23细胞外结构域，研究CDH23(S70P)与PCDH15的相互作用及与钙离子的亲和力；体内观察erl小鼠毛细胞顶连接的特征及抗凋亡对顶连接的保护作用，为揭示人类DFNB12的发病机理提供新理论或对其防治提供新途径。

CDH23 and PCDH15 are the two interactomes of tip links, which regulate the mechanotransduction(MET) channels of hair cells in the organ of Corti in the cochlea. It was reported that the penetrance of human DFNB12 (nonsyndromic deafness) caused by missense mutations in CDH23 was much higher than that of USH1D, which may result from nonsense, splice-site, frame shift or missense mutations in Cdh23. However, interactions of CDH23 with PCDH15 in DFNB12 are not fully understood. In the past few years, we developed a novel mouse model (erl, er long, in Chinese) for DFNB12, which bears a mutation (208 T>C) in Cdh23 gene, causing an amino-acid substitution (S70P)in CDH23. The erl mice were characterized by progressive hearing loss beginning at postnatal day 27 (P27)and being absolutly deafness at P90. Coordinatly, out hair cell(OHC) loss in the erl mice became progressively worse over the time and moved from the cochlear base to the apex. The progressive loss of hearing and OHCs in the erl mice provides a period for mechanistic study and drug intervention to preserve hearing. We hypothesize that alteration in the structures and adhering properties of CDH23 may lead to disruption of tip links, which is responsible for the erl's hearing loss. In this project, therefore, we will prepare the recombinant ectodomains (ECs) of CDH23(S70P) and PCDH15, and observe the interaction of CDH23(S70P) with PCDH15 and the affinity of CDH23(S70P) with Ca+2. We will also have a time-course observation of the features of tip links and the preserving effects on tip links by anti-apoptostic procedures, in the erl mice. The results from this study may aid in providing a new theory on the development of DFNB12 or finding new ways to prevent and treat the diseases.