Hippo-YAP通路调控鼻息肉上皮干细胞异常增殖和分化的机制研究

Studies have shown that the development of nasal polyps (NP) are closely related to the epithelial remodeling. We have shown that nasal epithelial stem cells (NESCs) derived from NP had reduced growth and proliferation dynamics in vitro culture, and differentiated into ciliated cells with impaired cilia architecture and ciliogenesis. Further studies demonstrated that NESCs were involved in the aberrant damage repair process of the epithelial remodeling in NP. Hippo-YAP pathway is a newly discovered pathway controlling the growth, and plays important roles in the regulation of stem cell function and tissue regeneration. Previously we found that a higher expression of YAP in NP, and LPS was able to activate the hippo-YAP pathway in NESCs. Thus, we hypothesize that the aberrant proliferation and differentiation of NESCs could be regulated via the hippo-YAP pathway, which may result in the epithelial remodeling. In this study, we intend to investigate the mechanism of the hippo-YAP pathway in regulating aberrant proliferation and differentiation of NESCs and explore its upstream signaling and downstream target genes, using the NESCs gas - liquid interface culture system, and a silencing and overexpression of the hippo-YAP pathway component strategy. We aim to unravel the effect and mechanism of the hippo-YAP pathway in the epithelial remodeling of NP, providing new targets and strategy for the improvement or reversal of NP epithelial remodeling.

研究表明鼻息肉（NP）发生发展和上皮重塑密切相关，我们已证明鼻息肉上皮干细胞（NESCs）在体外培养时增殖能力显著下降，诱导的纤毛细胞出现明显的纤毛结构不良和纤毛形成障碍；进一步研究发现NESCs参与了NP上皮异常损伤修复的重塑过程。hippo-YAP是新近发现的一个控制生长的通路，在调控干细胞功能、组织再生具有重要作用。我们先前发现NP高表达YAP，且LPS可激活NESCs的hippo-YAP通路。据此我们提出：hippo-YAP通路可能通过调控NESCs的异常增殖和分化而导致NP上皮重塑。我们拟通过NESCs气-液界面培养体系，采用沉默和过表达hippo-YAP通路组分的策略，研究hippo-YAP通路调控NESCs增殖和分化的效应和机制，并探讨其上游信号、下游调控靶基因，以期揭示hippo-YAP通路在NP上皮重塑中的作用和机制，为改善/逆转NP上皮重塑提供新的干预靶点和思路。

文献报告和我们前期研究发现，鼻息肉上皮干细胞存在显著的异常增殖，并且参与了鼻息肉上皮异常损伤修复的重塑过程，和正常鼻黏膜相比，鼻息肉上皮干细胞中hippo通路高表达，hippo-YAP通路可能介导和调控了鼻息肉上皮重塑过程中上皮干细胞的异常增殖和分化，其中LPS是可激活上皮干细胞hippo-YAP通路的信号之一。通过进一步研究，我们首次将具有调节细胞增殖与凋亡作用的hippo-YAP 通路引入鼻息肉的机制研究，以一种全新的研究思路，深入探讨分析，具体地：1）提出hippo-YAP 通路在鼻息肉中过度表达，主要效应转录因子Yes 相关蛋白（Yes associated protein，YAP）表达增高，主要以在上皮基层核内表达为主，促进鼻息肉上皮细胞增殖和组织重塑；2）提出了YAP蛋白表达增高可能是鼻息肉难治的原因，是临床上值得关注的治疗靶点，提出了鼻黏膜上皮干细胞是鼻黏膜上皮细胞异常增殖分化的源头，YAP促进了基底细胞像杯状细胞分化，抑制像纤毛细胞分化，导致鼻黏膜上皮细胞异常增殖、组织水肿、纤毛分化不良，最终导致上皮重塑、息肉形成。3）提出了基于全自动数字玻片扫描人工智能深度学习自动识别慢性鼻窦炎伴鼻息肉病理分型的技术，并申请发明专利3项，同时开放一种通过云端进行多范围人工智能自动识别鼻息肉病理类型的平台；4）提出在临床上鼻息肉导致的嗅觉敏感度下降与男性勃起功能障碍相关。综上所述，本研究聚焦鼻息肉，联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难以根据病理分型精准治疗的难题，取得一定的成效。