Notch 信号调控CCP110影响鼻纤毛生长与上皮细胞选择分化的机制研究

鼻窦黏液纤毛清除功能受损是慢性鼻鼻窦炎（CRS）的重要发病机制，CRS鼻窦粘膜表现为纤毛破坏及纤毛上皮细胞和杯状细胞比例失调，而炎症损伤后鼻窦粘膜纤毛生长和上皮细胞的选择性分化程度决定CRS的转归。中心粒蛋白110（CCP110）是影响纤毛生长过程的关键蛋白，我们首次报道CCP110可能抑制鼻窦粘膜纤毛生长过程，但其是否影响纤毛上皮细胞的选择性分化，尚无报道。有研究发现Notch信号可下调中心粒结构蛋白Multicilin调控呼吸上皮细胞的纤毛生长和选择性分化,而我们亦证实，炎症损伤后的鼻窦粘膜纤毛上皮细胞生长过程中存在Notch信号的活化。因此，本研究拟明确CCP110及Notch信号在炎症损伤后鼻窦粘膜纤毛生长和上皮细胞选择性分化过程中的作用，进一步探讨在炎症状态下CCP110与Notch信号之间的相互关系，从而阐明CRS纤毛生长及上皮细胞选择性分化的分子机制，为CRS临床研究提供依据

Chronic rhinosinusitis (CRS) is a multifactorial disease and so far the exact mechanism is still unclear, but the last sequeanci is the damage of sinonasal epithelial mucociliary clearance system. Multiple reports have demonstrated that sinonasal mucosa from patients with CRS with and without nasal polyposis have significant morphologic changes compared with control mucosa, such as an abundance of nonciliated cells and ciliated cells with short or abnormal cilia. We have previously identified that increased Centriolar coiled coil protein 110 (CCp110) expression in mucosa from patients with CRS might contribute to the poor ciliation observed in patients with CRS. Higher CCp110 expression might block the ciliogenesis in injury sinonasal epithelial ciliated cells providing a greater insight into the pathogenesis of CRS. Notch pathway is known to regulate cell fate in many contexts and was proved to involve in the abnormal airway epithelial cell differentiation. However, its role in the ciliogenesis of the sinonasal epithelial ciliated cell is still unclear. Our pre-trial data showed that the expression of receptors of Notch pathway in the sinonasal epithelial ciliated cells could be up-regulated by inflammation factors. Here we would like to investigate the relationship between the Notch pathway and expression of CCP110 during the differentiation in sinonasal epithelial ciliated cells, even in an exogenous cytokine exposure condition. Then we will further discuss the underlie mechanism on CCp110's working in the process of ciliated cell trans-differentiation and ciliogenesis through the Notch pathway, which might give a new direction for understanding the pathogenesis and offer a novel target in the management for CRS.