银屑病中CCN1入核介导角质形成细胞增殖的机制研究

Psoriasis is a inflammatory skin disease，characterized by epidermal proliferation and erythematous scaling. The mainly pathological change is the abnormal proliferation and differentiation of epidermal keratinocytes, indicating that its pathogenesis may be related to cell apoptosis, proliferation and differentiation, and disorder of cycle regulation. CCN1 is an extracellular secretory matrix protein, which is currently recognized as a proinflammatory factor in the world. Our previous study has found that a considerable amount of CCN1 appeared in the nuclei of psoriatic lesional keratinocytes, and in vito experiment has confirmed inflammatory microenvironment can promote CCN1 translocation into the cell nucleus, which has no obvious effect on the expression of inflammatory factors (such as CCL20, IL-8 and IL-1β) , but can significantly promote keratinocyte proliferation. Therefore, based on the existing results, the project designed here intend to explore the relationship between CCN1 nuclear distribution and psoriasis patients severity, and the molecular mechanism involved in the hyperproliferation of keratinocyte by CCN1 in nucleus. It provides theory foundation for the involvement of CCN1 protein in the pathogenesis of psoriasis, suggesting that CCN1 may be a potential therapeutic target for patients with psoriasis. Collectively, our study is very important with scientific significance and greater potential value in clinical diagnosis and treatment.

银屑病是一种以表皮增殖、红斑鳞屑为特征的炎症性皮肤病，病理改变主要是表皮角质形成细胞的增殖分化异常，表明其发病可能与细胞凋亡及增殖分化、周期调控紊乱相关。CCN1是一种分泌型基质蛋白，目前国际上公认CCN1同时还是一种促炎因子。前期研究发现CCN1大量出现在银屑病皮损处角质形成细胞的胞核中，体外实验证实炎性微环境能够促进CCN1进入角质形成细胞的胞核，CCN1入核后对炎症因子CCL20、IL-8和IL-1β的表达没有影响，却能显著性促进角质形成细胞的增殖。因此本项目拟在已有的工作基础上，系统分析CCN1核分布情况与银屑病病情的关系及其在胞核中促进角质形成细胞增殖的分子机制，为发展临床诊治新靶点提供有力的依据，具有重要的科学意义和应用价值。

银屑病是一种常见的由免疫介导的鳞屑性皮损为主要特征的慢性炎症性皮肤疾病，病理改变主要是表皮角质形成细胞的增殖分化异常，表明其发病可能与细胞凋亡及增殖分化、周期调控紊乱相关；另外皮损部位浸润的多种免疫细胞如中性粒细胞、巨噬细胞、Th17与多种细胞因子尤其是IL-23、IL-17等相互作用导致的炎性微环境在银屑病的发生发展中也起着重要作用。CCN1是一种分泌型基质蛋白，目前国际上公认CCN1同时还是一种促炎因子。研究中我们发现分泌性蛋白CCN1大量出现在银屑病皮损处角质形成细胞的胞核中，体外构建不同长度的CCN1截断体，转染后发现CCN1的CT结构域与CCN1蛋白在胞核中的定位密切相关，表明CT结构域可能存在核定位序列；进一步体外实验证实炎性微环境能够促进CCN1进入角质形成细胞的胞核，CCN1入核后对炎症因子CCL20、IL-8和IL-1β的表达没有影响，却能显著性促进角质形成细胞的增殖，提示CCN1入核后可能发挥转录因子作用。另外我们还发现在银屑病早期的皮损部位IL-23和中性粒细胞存在明显的共定位，CCN1可以作用于中性粒细胞表面的整合素受体激活P38和NF-κβ通路调控IL-23的产生。上述研究有助于从全新角度阐释CCN1蛋白通过倚重不同的信号途径（胞外作用和胞核作用）和作用于不同的细胞（组织细胞和免疫细胞）参与银屑病的发生和发展，为治疗银屑病提供新的理论和实验依据，为开发新的银屑病靶向阻断药物提供支持。