白介素-1受体相关激酶(Interleukin-1 receptor associated kinase,IRAK)-M调节哮喘气道炎症异质性和气道重塑以及相关机制的研究
结题报告
批准号:
81970025
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
高金明
学科分类:
支气管哮喘
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
高金明
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中文摘要
哮喘气道炎症有异质性,白介素-1受体相关激酶(IRAK)-M表达于气道上皮,抑制了TLR通路,但双向调节炎症反应。OVA诱发的哮喘模型发现,急性期IRAK-M KO增强APC表达共刺激分子,诱导Th2细胞分化,加重Eos和Th2优势的气道过敏炎症;慢性期IRAK-M KO增强了APC表达共抑制分子,促进Th1功能,减轻Eos和Neu优势的气道炎症及重塑。我们将探讨IRAK-M在吸入过敏原HDM诱导的气道炎症异质性中作用机制: (1) IRAK-M如何通过气道上皮-树突细胞“交流 ”影响气道上皮炎症、DC摄取抗原并被激活以及T细胞激活和分化;(2) IRAK-M易感功能性SNP对Th2因子表达的作用;(3) IRAK-M对成纤维细胞侵袭气道的影响及其机制;IRAK-M对气道平滑肌增殖、收缩和迁移的作用。本申请从气道起源探讨哮喘的机制,提出在不同时相调节气道免疫分子,为哮喘治疗带来新思路。
英文摘要
Asthma is characterized by heterogeneous airway inflammation and regarded an airway epithelial disorder. Airway epithelial cells (AECs) expressing intracellular interleukin-1 receptor associated kinase (IRAK)-M functions as a negative regulator of NF-kB, however, has been demonstrated a distinctive role in regulating inflammation. Our recently published works, using OVA to induce asthma model in IRAK-M knockout mice, found that: (1) in an acute model, IRAK-M deficiency increased expression of costimulatory molecules by APCs, induced Th2 differentiation, attenuated allergic airway inflammation predominated by Eosinophils and Th2 cells; in a chronic model, IRAK-M ablation increased expression of coinhibitory molecules by APCs, promoted Th1 cells function, lessened chronic airway inflammation predominated by the mixed type of Eosinophils and Neutrophils and airway remodeling. These encouraging data drive us to further study the possible mechanisms of IRAK-M in modulating the heterogeneity of airway inflammation induced by acute and chronic exposure to environmental allergen HDM, including the impact of IRAK-M on cellular inflammation of lung epithelial cells through epithelium-dendritic cells (DCs) cross-talk, antigen uptake by DCs and DCs activation, and T cell activation. We will also study the effect of two identified IRAK-M susceptible SNPs on Th2 cytokine secretion. Airway structural change is a typically physiological characteristic of asthma. Based our previous results, this proposal will involve the influence of IRAK-M in mediating airway fibroblasts invasion into the airways and relevant mechanisms, and the role of IRAK-M in proliferation and migration of airway smooth muscle co-cultured with airway epithelial cells. The goals presented in this proposal will be helpful in widening our understandings in airway inflammation from the origin of asthma pathogenesis --- how the innate immunity of the airway epithelium initiates airway inflammation. Appropriate modulation of innate immunity molecules expressed by the airways at the different disease context will provide a novel insight into asthma pharmacotherapy.
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DOI:10.1186/s12920-023-01545-4
发表时间:2023-05-23
期刊:BMC medical genomics
影响因子:2.7
作者:
通讯作者:
IRAK-M Regulates Proliferative and Invasive Phenotypes of Lung Fibroblasts
IRAK-M 调节肺成纤维细胞的增殖和侵袭表型
DOI:10.1007/s10753-022-01772-4
发表时间:2022-12
期刊:Inflammation
影响因子:5.1
作者:Zhoude Zheng;Jia Li;Ye Cui;Wei Wang;Mingqiang Zhang;Youming Zhang;Yan Bai;Sun Ying;Jinming Gao
通讯作者:Jinming Gao
DOI:10.21037/jtd-22-820
发表时间:2023-02-28
期刊:Journal of thoracic disease
影响因子:2.5
作者:
通讯作者:
DOI:10.1186/s12931-023-02406-5
发表时间:2023-04-07
期刊:Respiratory research
影响因子:5.8
作者:
通讯作者:
支气管上皮的基因和环境相互作用对哮喘表型的影响:哮喘发病机制的探讨
趋化因子受体CXCR3在吸烟诱导的慢性阻塞性肺病中的作用和相关机制的研究
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海外基金