重症哮喘虽然仅占哮喘人群总数的3-10%，但其急诊就医率和住院率分别为轻中度哮喘的15和20倍，给社会带来沉重的经济负担。β-Catenin介导支气管上皮-间质样转化（EMT）异常，并继发气道重塑是哮喘患者病情加重的主要原因，但其潜在机制未明。酪氨酸磷酸酶SHP-1是细胞内信号传导的负调控因子，在重症哮喘气道炎症和气道高反应性中起重要作用。本项目预实验已证实，支气管上皮SHP-1缺陷可诱导β-Catenin酪氨酸残基654位点（Y654）过度磷酸化修饰，并在EMT中发挥关键作用。因此，我们提出科学假说：支气管上皮细胞SHP-1可能通过抑制pY654-β-Catenin过表达，调控EMT进程，进而延缓气道重塑的发生发展。为验证这一假说，本项目将从细胞、动物及人体标本多方面明确SHP-1在气道重塑中的作用，并探讨SHP-1调控β-Catenin/EMT信号通路的机制，为防治重症哮喘提供新思路。

Severe asthma comprises 3-10% of the patients with asthma, but its emergency visits and hospitalization rates were 15 and 20-fold higher than mild and moderate asthma, respectively, which has brought a serious economic burden to the social medical care system. Airway remodeling, induced by abnormal β-Catenin-mediated bronchial epithelial-mesenchymal transition (EMT), is the main cause of severity in asthmatic patients. However, its underlying mechanism is still unknown. Tyrosine Phosphatase SHP-1, a negative regulator of intracellular signaling, plays a critical role in airway inflammation and airway hyperresponsiveness in severe asthma. Our preliminary study has confirmed that SHP-1 deficient could induce β-Catenin hyperphosphorylation at tyrosine residue 654 (Y654) in bronchial epithelium, which plays a key role in EMT. Therefore, we speculated that SHP-1 may regulate EMT progress and further suppress airway remodeling through inhibiting pY654-β-Catenin overexpression in bronchial epithelial cells. To verify this hypothesis, this project will clarify the function of SHP-1 in airway remodeling, and explore the mechanism of SHP-1 on β-Catenin/EMT signaling pathway via multifaceted studies from cell lines, animal models, and human specimens, which will provide new ideas for the prevention and treatment of severe asthma.