长链非编码RNA在鼻息肉中的表观遗传学调控机制研究

Nasal polyps are heterogeneous chronic inflammatory condition of the nasal mucosa. Unlike in Caucasians, where nasal polyps show Th2 dominance and extensive eosinophils infiltration, in Asian people, including Chinese, a majority of nasal polyps are non-eosinophilic rather than eosinophilic subtype. Our previous studies have proved that key cytokine (IL-5，IL-17 & IFN-γ, etc)-negative nasal polyps are a major subtype, while IL-5+ nasal polyps takes up only 20% of the nasal polyps. It is hard to define the pathogenesis of nasal polyps in a single way due to its heterogeneity. Therefore, study on the epigenetic regulatory mechanism of nasal polyps from the gene regulation point of view may be able to explain the mechanism of the inflammation and tissue remodeling in nasal polyps. Currently, long non-coding RNAs (lncRNAs) have been proved to play an important role in immune response and airway inflammation. They are also demonstrated to be differently expressed with tissue and cell specificity in different nasal polyps in our preliminary stduy. Therefore, we suppose that the differently expressed lncRNAs may directly take part in the regulation of the inflammation and tissue remodeling in nasal polyps. Hopefully, the in-depth study on them may unveil the role of lncRNAs in the epigenetic regulation of the inflammation and tissue remodeling in nasal polyps, and provide a new breakthrough in the treatment of nasal polyps.

鼻息肉是一类异质性很大的黏膜慢性炎症，不同于西方白人以Th2细胞优势和广泛的嗜酸性粒细胞浸润为主，亚洲人群，包括中国，则发现嗜酸性息肉占少数，而多数为非嗜酸性息肉。我们的研究证实，国人中IL-5，IL-17和IFN-γ等主要细胞因子皆阴性者为一大类鼻息肉亚型，而IL-5+鼻息肉仅占约20%。鼻息肉的异质性导致其发病机制难以用一种方式进行解释。因此，从其基因调控的角度入手，深入研究其表观遗传学调控机制，有可能阐明鼻息肉炎症和组织重塑的发生发展机理。目前长链非编码RNA（lncRNA）已被证明在免疫反应和气道炎症中发挥着重要的作用，我们前期实验也证实lncRNA在不同类型鼻息肉中存在明显的差异表达。因此我们设想：鼻息肉中差异表达的lncRNA可能直接参与了鼻息肉炎症及组织重塑的调控。对其进行深入研究则有望揭示lncRNA在鼻息肉炎症及组织重塑中的表观调控机制，并为其治疗提供全新的切入点。

目前，鼻息肉的病因尚不完全清楚，发病机制仍未完全阐明，而在分子水平上，从基因调控的角度探究鼻息肉的发病机制已成为研究热点。长链非编码RNA（Long non-coding RNA，lncRNA）作为一种表观遗传调控方式，可能在鼻息肉的发生发展中具有作用，但鲜有文献报道。本研究依据组织细胞因子的表达情况，对鼻息肉进行分型，将其分为IL-5+NP和KCN两种亚型。根据前期进行的组织lncRNA基因芯片检测得到的结果，我们对差异表达的lncRNA在不同亚型鼻息肉中进行大样本验证实验，发现了16个可在对照组、IL-5+NP组和KCN组之间差异表达的lncRNA。进一步我们明确了TC441、N1873和N4208这三个lncRNA在组织中的定位，其中TC441在IL-5+NP组的黏膜上皮的表达量明显高于其他两组，表明其可能在鼻黏膜上皮中发挥作用。SEB刺激培养的鼻黏膜上皮细胞，明显诱导上述3个lncRNA的表达并上调IL-25、IL-33和TSLP的mRNA表达水平。最后我们发现在黏膜上皮的损伤过程中，TC441可能促进IL-25和TSLP的表达，参与鼻息肉的嗜酸化过程，但具体的作用机制还需进一步研究。总之，对lncRNA的作用机制进行深入研究，可能为鼻息肉的诊治提供新的理论依据。