上皮细胞紧密连接调控Hippo-YAP信号通路参与慢性鼻窦炎伴鼻息肉上皮重塑的机制研究

The development of nasal polyps (NP) is closely related to the epithelial remodeling, our previous study published on the journal Allergy firstly found that the Hippo-YAP pathway, which controlled the organ growth and tissue remodeling, involved in the epithelial remodeling of NP. However, the upstream signal is still unclear. Studies reported that tight junctions (TJs) can regulate the Hippo pathway. Our previous study found that the expression of TJs protein ZO-1 decreased in NP and associated with the aberrant differentiation of cilium, as well as with the high expression of YAP. Thus we put forward that the decreased expression of TJs may work as the upstream signal to regulate the activation of YAP during the epithelial remodeling of NP. The present study intends to detect the expression of ZO-1 and the Hippo pathway components before and after being stimulated by cytokines in vitro in the air-liquid interface culture system, and investigate the relationship with the aberrant proliferation and differentiation of epithelial cells. Moreover, we plan to interfere and overexpress the ZO-1 protein to investigate the regulation of TJs on the activation of YAP. We aim to unravel the regulation of TJs as the upstream signal on the Hippo pathway during the epithelial remodeling of NP, enriching the understanding of pathological mechanisms of NP and providing the new strategy and theoretical basis for the prevention and treatment of NP.

上皮重塑与鼻息肉(NP)发生密切相关，我们在杂志Allergy发表的文章首次发现控制器官大小和组织重塑的Hippo-YAP通路参与了NP的上皮重塑，但上游信号不明。文献报道上皮细胞紧密连接（TJs）可调控Hippo通路，我们预实验发现TJs蛋白（ZO-1）在NP中表达下降与NP纤毛分化不良有关，且ZO-1表达下降时YAP高表达，据此我们提出TJs表达下降可能为活化YAP表达的上游信号。本研究拟通过气-液界面细胞培养体系，采用炎症因子体外刺激检测NP上皮细胞ZO-1及Hippo各组分表达，分析与上皮细胞增殖及纤毛分化的相关性。通过干扰和过表达ZO-1的策略探讨TJs对YAP活化的调节作用，目的为验证TJs作为Hippo通路上游信号调节NP上皮重塑的作用。研究结果有助于丰富NP发病机制的研究，为NP的临床防治提供新的方向和依据。

文献报告发现鼻息肉存在上皮细胞异常增殖，我们前期研究发现和正常鼻黏膜细胞相比，鼻息肉上皮细胞中hippp-YAP通路高表达，提示核心蛋白YAP可能介导和调控了鼻息肉上皮异常增殖。文献报告提示上皮紧密连接受损可能为Hippo-YAP通路的上游信号，我们首次探讨鼻息肉上皮紧密连接受损是否可调控YAP蛋白，通过进一步研究发现，在2型炎症因子IL-13影响下，鼻息肉上皮存在紧密连接蛋白的功能及表达下降，为鼻息肉上皮细胞异常增殖和组织重塑的一个重要病因，但是否为激活Hippo-YAP通路上游信号仍需进一步探讨，综述所述，本研究聚焦鼻息肉上皮紧密连接受损，结合基础研究和临床问题分析，一定程度上解释了鼻息肉的发病机制和重视上皮屏障问题。