CP110调控鼻黏膜上皮细胞多纤毛发生以及纤毛结构异常的功能和机制

鼻黏膜上皮纤毛清除功能下降导致和加重黏膜慢性炎症。我们在JACI文章揭示鼻息肉上皮纤毛结构异常（密度和长度增加）是造成纤毛功能下降主要原因，并发现单纤毛发生的关键中心粒蛋白CP110表达升高与异常的纤毛结构密切关联；细胞实验表明CP110在纤毛基体部，并在鼻息肉来源的纤毛细胞中高表达；但CP110在鼻上皮细胞多纤毛发生的调控机制依然不明。我们推测CP110表达的异常可能影响多纤毛的发生，进而在炎症黏膜上皮中导致纤毛结构和功能的异常。本项目拟通过体外正常和炎症来源的原代鼻上皮干细胞-分化细胞模型，采用细胞生物学、基因沉寂和过表达等手段阐明CP110在鼻上皮多纤毛发生的调控机制及其在纤毛异常结构的功能和作用；同时探讨CP110关联的重要中心粒蛋白在鼻多纤毛发生的作用；预期将从根源上解释鼻上皮纤毛在生理和炎症条件下的发生机制，为确立以CP110作为关键靶点改善纤毛特性和功能提供重要的科学依据。

The aberrant ciliary function in nasal mucosa is critical for the development of chronic mucosal inflammation. Our recent paper (published in J Allergy Clin Immunol) has revealed that abnormal ciliary architecture (longer and dense cilia) should be an essential reason for the dysregulation of ciliary function in human nasal polyps, and an increase of CP110 which was the key centriolar protein in primary ciliogenesis was associated with the abnormality of ciliary structure; in vitro experiment demonstrated that CP110 expressed in the cilia basal body and CP110 expression level was higher in the nasal polyp derived epithelial cells than those from the healthy nasal mucosa; nonetheless, the exact regulation roles of CP110 in nasal epithelial multiciliogenesis remain unclear. We hypothesize that the aberrant expression of CP110 may affect the multiciliogenesis in human nasal epithelial cells, and then lead to an abnormal ciliary architecture in the epithelium under nasal mucosal inflammation. This project will utilize the human nasal stem and differentiated cell model, and use several cell biological, gene silencing, and overexpression techniques and methods to clarify the regulation mechanism of CP110 in nasal multiciliogenesis and the functions/roles of CP110 in abnormal ciliary structure; we also explore the roles of important CP110 relevant centriolar proteins in nasal multiciliogenesis. The results will explain the fundamental mechanism of nasal cilia development and assembly under healthy and inflammatory mucosa, and contribute to the development of CP110 as specific targets for the improvement of cilia properties and function under chronic nasal mucosal inflammation.