Shh信号通路对CCL2调控在哮喘发生中的作用和机制研究

Bronchial asthma (asthma) is a common chronic inflammatory disease of the airways characterized by airway hyperresponsiveness. Our previous studies demonstrated that Sonic hedgehog (Shh) signals and CC chemokine ligand 2 (CCL2) are involved in asthma pathogenesis. Moreover, Shh signaling pathway participates in the regulation of CCL2 expression. CCL2 is a monocyte chemotactic factor, which promotes monocytes activation and migration into the lungs to become bronchoalveolar macrophages (BAMs). However, the effect and molecular mechanism of Shh signals on the regulation of CCL2 signaling pathway is still unclear. In this study, we plan to use the OVA-induced asthma model and the mice model with doxycycline-induced Smo (Shh receptor) conditional knockout in Clara cells in the terminal bronchioles and respiratory bronchiole, to investigate the effect of Shh signals on the regulation of CCL2 signals and BAMs. Also, we investigate the molecular mechanism using cell model in vitro. Moreover, we will investigate the practical role of Shh inhibitor on treatment of the hyperresponsiveness by reducing the airway inflammation and airway remodeling in asthma. This study will bring a new insight into the mechanism, prevention and intervention of asthma.

支气管哮喘（哮喘）是一种常见的以气道高反应性为特征的气道慢性非特异性炎症性疾病。我们前期研究表明Sonic hedgehog（Shh）信号和CC趋化因子配体2（CCL2）参与哮喘发病，且Shh信号通路参与肺部CCL2的表达调控；CCL2是单核细胞趋化因子，可促使单核细胞活化、迁移入肺部成为支气管肺泡巨噬细胞（BAMs）。然而，在哮喘发病中，Shh信号通路调控 CCL2信号的分子机制尚不清楚。本课题拟在OVA诱导建立哮喘模型的基础上，利用强力霉素诱导的终末细支气管和呼吸性细支气管Clara细胞中Smo基因（Shh受体）敲除小鼠，研究Shh信号在哮喘发病机制中对气道CCL2信号通路和BAMs的调控效应；利用体外细胞模型进一步明确Shh信号调控CCL2信号通路和BAMs的分子机制；并研究Shh信号抑制剂改善气道炎症和重塑在哮喘气道高反应性治疗中的实际意义,这将为哮喘发病机制和防治提供理论依据。

支气管哮喘（哮喘）是一种常见的以气道高反应性为特征的气道慢性非特异性炎症性疾病。我们在前期研究基础上，探讨Shh在哮喘发病中的效应和机制，主要侧重Shh信号通路对CCL2等炎性信号通路中的作用和机制。研究发现LPS、IL-4和IL-13等可促使气道上皮细胞Shh信号表达，其中IL-4和IL-13主要通过JAK-STAT6信号通路发挥作用。哮喘儿童支气管肺泡灌洗液（BALF）细胞中CC趋化因子配体2（CCL2）表达上调，体外试验显示Shh不仅可以上调支气管上皮CCL2表达，还可以促使巨噬细胞CCL2表达，Shh信号通路抑制剂可逆转相关基因表达。LPS还可促进巨噬细胞CCL2和MCPIP表达。我们还同时发现Shh可以促使巨噬细胞其他炎症因子（如IL-1β、IL-8、TNF-α、eotaxin和visfatin等）表达；非编码RNA（如hsa_circ_0001947和hsa_circ_0001947）也可能参与哮喘发病机制（黏蛋白表达）。这为更全面认识哮喘发病机制，哮喘治疗新靶点探讨提供理论依据。