高等动物运动纤毛中央微管座的组分和功能研究

在高等动物体内如气管、脑室管膜以及输卵管等上皮组织，其多纤毛的周期性摆动可湿润、清洁气管、驱动脑脊液流动和受精卵运动。多纤毛发生和功能的异常可导致不孕、气管炎和脑积水等遗传缺陷。多纤毛是以轴丝的九组二联体微管和一对中央微管为核心形成精美、复杂的运动器械，但其精细结构的形成机理仍不清楚。中央微管是纤毛运动的传感器，申请人在前期研究中发现其底部存在一特殊的柱状结构，其中特异性地含有Cep131和非基体定位的Centrin。我们推测该结构很可能为其中央微管提供锚定和支撑，因此命名为“中央微管座”。我们构建了Cep131的基因敲除小鼠，发现其脑室多纤毛缺乏中央微管座，而且一部分纤毛失去了运动能力，提示该结构具有重要功能，且Cep131是其形成的关键蛋白质。本项目将在前期研究的基础上，对中央微管座这一自主发现的新结构的组分、形成机理和功能进行深入研究，扩展对运动纤毛结构、组装和调节机制的认识。

Epithelial tissues such as those in mammalian trachea, ependyma, and oviduct, the periodic beating of its multicilia can moisturize and clean the trachea, drive the ependymal flow and the movement of the fertilized egg. Abnormalities in biogenesis and function of multicilia can lead to genentic defects such as infertility, bronchitis and hydrocephalus. Multicilia are delicate motile machineries consisting of the “9 + 2” microtubule arrays and central pair (CP) microtubules, and how they are accurately assembled is poorly understood. The central pair microtubules is the sensor of ciliary motility. In the previous study, the applicant found a special columnar structure specifically containing Cep131 and non-basal body-oriented Centrin, was at the base of central pair microtubules. We speculate that this structure is likely to provide anchoring and supporting for central pair microtubules, which we term as “CP-foot”. We constructed Cep131 knockout mice and found that their ependymal cilia lacked CP-foot and partially multicilia lost motility, suggesting that this structure has important functions and that Cep131 is the key component for its formation. Based on the previous research, this project will conduct in-depth research on the composition, formation mechanism and function of the independently discovered new structure of CP-foot, and expand the understanding of the structure, assembly and regulation mechanism of motile cilia.