miR-375调控TSLP-JAK信号轴介导循环纤维细胞骨架重构在哮喘气道重塑中的作用

项目名称： miR-375调控TSLP-JAK信号轴介导循环纤维细胞骨架重构在哮喘气道重塑中的作用

项目编号： No.81470219

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈壮桂

作者单位： 中山大学

项目金额： 75万元

中文摘要： 气道重塑是哮喘治疗的难点，可导致患者死亡，探明其发病机制刻不容缓，而循环纤维细胞（CF）在气道组织浸润、转分化为肌成纤维细胞是其突出的病理特征。因此，揭开CF自外周循环迁移入气道组织的分子机制至关重要。我们已证实，气道上皮细胞损伤后，分泌的胸腺基质淋巴细胞生成素（TSLP）是启动和维持气道重塑关键的因子（PLoS One.e51268,2013）。但是TSLP上游的调控信号是什么？TSLP又通过哪个下游信号通路激活效应细胞？受课题预实验和TSLP在异位性皮炎、间充质干细胞方面研究成果的启发，我们拟通过体内外实验，验证外界环境损伤因子通过内源性信号miR-375上调TSLP过表达，进而激活JAK/STAT通路，引起CF骨架重构，使其由外周迁移到气道并在组织浸润，参与气道重塑的创新性假设。课题设计开拓了从细胞运动的角度探索气道重塑发病机制的新思路，预期结果有望为突破哮喘治疗的瓶颈提供干预靶点。

中文关键词： 重症哮喘；气道重塑；胸腺基质淋巴细胞生成素；信号通路；循环纤维细胞

英文摘要： Clinical trials of therapeutic intervention to prevent asthmatic airway remodeling are currently lacking. Since airway remodeling in asthmatics can ultimately lead victims to death, to explore the mechanisms underlying its pathogenesis admits of no delay. The most important pathologic feature of airway structural alterations in severe asthmatics is circulating fibrocytes's migration and recruitment in airway. Recruitment of circulating fibrocytes from the peripheral circulation to the airway tissues and its transdifferentiation into myofibroblasts are crucial in asthmatic airway remodeling process. In this context, it is necessary to expound the mechanism how environmental damage factors to initiate and mediate the migration of circulating fibrocytes to airway tissues. We have demonstrated that upregulated TSLP, an epithelium-derived cytokine, resulted in airway remodeling of asthmatic mice (PLoS One. 2013:e51268.). However, the questions that, what is the upstream regulator of TSLP and what is the downstream effector cell of TSLP, are still unclear. The ideas of this study come from our preliminary experiments and the roles that TSLP played in atopic dermatitis and mesenchymal stem cells. In the present project, in vivo and in vitro models will be designed to test our hypothesis, and reveal how damage signals from epithelial cells to upregulate TSLP expression by miR-375, then activate JAK/STAT pathway in circulating fibrocytes, mediate cells skeleton structure reconsititution, drive circulating fibrocytes to immigrate in and participate in airway remodeling process. The development of this project will provide a new insight between cells movement and pathogensis of asthmatic airway remodeling, and could significantly contribute to investigate potential targets and strategies for clinical interventions of asthmatic airway remodeling, which may consequently improve the treatment for chronic asthma.

英文关键词： severe asthma;airway remodeling;TSLP;signal pathway;circulating fibrocytes