静纤毛是位于耳蜗内耳毛细胞的顶端，是听觉发生时把机械信号（声波）转化为电信号（细胞去极化从而形成受体电位）的重要场所；微绒毛位于小肠等的上皮细胞上，起到增大细胞表面从而实现利于细胞的吸收功能。它们都是以微丝为骨架的亚细胞结构，其非正常发育及形貌病变会导致多种遗传性疾病。我们近期的研究发现，控制静纤毛和微绒毛的发育和组装的蛋白质复合物具有高度的相似性，称为顶端连接复合物。本项目将进一步详细研究顶端连接复合物的组装及定位机制，包括解析Harmonin/CDHR2复合物结构以了解Harmonin CC1在复合物组装中的作用机理、以及寻找SANS/ANKS4B ANK的结合蛋白以了解顶端连接复合物的定位机制。这些研究成果将为我们深入理解静纤毛/微绒毛的发育与维持提供分子层面的结构信息，阐明遗传性耳聋和遗传性肠道疾病等的致病机制，填补基因突变与疾病症状间的空白，并为未来可能的治疗提供前期的积累。

Stereocilia locate at the apical surface of hair cells in cochlea, responsible for transforming the mechanical signal (sound wave) to electrical signal (membrane potential causing by opening of the ion channels and depolarization of the cells). Microvilli locate at the outer surface of epithelial cells of small intestine, responsible for increasing cell surface for nutrient uptake. They are both actin filaments-based subcellular structures. Developmental defects or morphological changes of these structures are closely related to inherited disease such as deafness, blindness and enteropathy. Our recent studies demonstrated that the protein complex, called Tip-link complex, controlling the assembly of stereocilia and microvilli are highly similar to each other. In this proposal, we plan to further investigate the assembly and targeting mechanism of Tip-link complex. The plan includes solving the structure of Harmonin/CDHR2 complex to understand how Harmonin CC1 is involved in the complex assembly and searching for binding partners of SANS/ANKS4B ANK to understand the targeting mechanism of Tip-link complex. We hope that our discoveries will provide insights into the molecular basis of how stereocilia/microvilli develop and maintain, elucidate the disease-causing mechanism of inherited haring loss or enteropathy, bridge the gap between genetic mutations and clinical symptoms, and finally benefit the future treatments of such diseases.