Role of allergen-driven epithelial genes in asthma pathogenesis

过敏原驱动的上皮基因在哮喘发病机制中的作用

• 批准号: 8196246
• 负责人: Marsha Wills-Karp
• 金额: $ 36.12万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196246
• 关键词: Acute; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Amplifiers; Antigen-Presenting Cells; Area; Asthma; Atopic Dermatitis; Automobile Driving; Basophils; Cells; Child; Childhood; Clinical; Collaborations; Custom; Data; Data Analyses; Development; Disease; Disease susceptibility; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Epithelium; Etiology; Event; Extrinsic asthma; Family member; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Human; Immune; Immune response; Immunity; In Vitro; Individual; Interleukin-1; Interleukin-13; Interleukin-4; Lead; Lung; Mediating; Messenger RNA; Metaplasia; Molecular; Mucous body substance; Mus; Nose; Ohio; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiologic pulse; Physiological; Play; Population; Predisposing Factor; Predisposition; Process; Production; Proteins; Public Health; Recruitment Activity; Reporting; Resources; Risk; Role; Societies; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Variant; airway epithelium; airway hyperresponsiveness; allergic airway disease; allergic response; base; cell injury; cohort; cytokine; data integration; defined contribution; eosinophil; eosinophilic inflammation; gene interaction; macrophage; mast cell; novel; programs; receptor; repaired; response; trefoil factor

Allergic diseases continue to pose a significant public health burden in modernized societies. Although the etiology of allergic diseases is unknown, they are thought to develop as a result of aberrant Th2 immune responses in genetically susceptible individuals. Despite this recognition, the factors driving Th2-mediated immune responses have remained elusive. Our preliminary data suggests the novel paradigm that allergen exposure induces epithelial cell injury which results in the release of an epithelial-derived factor, trefoil factor 2. Tff2, in turn induces the release of the "alarmin" IL-33, which drives Th2 cytokine production in innate immune cells. The production of Th2 cytokines, amplifies and perpetuates the response by driving additional Tff2 release. Importantly, we show that TFF2 levels are elevated in epithelial cells from asthmatic children undergoing an acute attack as compared to cells from healthy controls. Thus the goal of this proposal is to test the novel hypothesis that aberrant epithelial cell production of TFF2 is important in the induction and expression of Th2-mediated allergic responses in an IL-33-dependent manner. Moreover, we propose that genetic variation in the genes controlling this pathway (TFF2, IL-33, IL-1RL1) enhances the risk of developing allergic diseases (allergic asthma, atopic dermatitis, allergic rhinitis, eosinophilic esphagitis) in children. To test this hypothesis, we propose the following specific aims: 1) To determine the contribution of the Tff2/IL-33 pathway to the initiation of Th2-mediated allergic airway responses; 2) To determine the mechanism by which TFF2 mediates IL-13-dependent AHR and mucus cell metaplasia; and 3) To determine whether dysregulation of the TFF2/IL-33 pathway contributes to the risk of developing allergic disorders in cohorts of children recruited from the Cincinnati Area. The studies in this Project are closely aligned with and benefit from the resources and information generated in Projects 1 and 2 of this U19, which are also focused on defining the contribution of altered mucosal epithelial function in the etiology of allergic diseases. Identification of the Tff2/IL-33 pathway as an important driver and amplifier of the allergic response should lead to the development of disease modifying therapies for the treatment of allergic disorders.

在现代化社会中，过敏性疾病继续构成重大的公共卫生负担。虽然 过敏性疾病的病因尚不清楚，它们被认为是由于异常的Th 2免疫应答而发展的。 遗传易感个体的反应。尽管有这种认识，驱动Th 2介导的 免疫反应仍然难以捉摸。我们的初步数据表明过敏原 暴露诱导上皮细胞损伤，导致上皮衍生因子三叶因子的释放 2. Tff 2反过来诱导“alarmin”IL-33的释放，其驱动先天性免疫缺陷细胞中Th 2细胞因子的产生。 免疫细胞Th 2细胞因子的产生通过驱动额外的细胞因子而放大和延续应答。 TFF 2释放重要的是，我们发现哮喘儿童上皮细胞中的TFF 2水平升高， 与来自健康对照的细胞相比，经历急性发作。因此，本提案的目的是 测试新的假设，即TFF 2的异常上皮细胞产生在诱导中很重要， 以IL-33依赖性方式表达Th 2介导的过敏反应。此外，我们建议， 控制这一途径的基因（TFF 2、IL-33、IL-1 RL 1）的遗传变异增加了 发生过敏性疾病（过敏性哮喘、特应性皮炎、过敏性鼻炎、嗜酸性食管炎）， 孩子为了验证这一假设，我们提出了以下具体目标：1）确定 Tff 2/IL-33通路对Th 2介导的过敏性气道反应的启动; 2）为了确定Tff 2/IL-33通路对Th 2介导的过敏性气道反应的启动作用， TFF 2介导IL-13依赖性AHR和粘液细胞化生的机制;以及3）确定 TFF 2/IL-33通路的失调是否会导致过敏性疾病的发生， 从辛辛那提地区招募的一群儿童。本项目的研究与 受益于U19项目1和2中产生的资源和信息，这些资源和信息也集中在 关于定义粘膜上皮功能改变在过敏性疾病病因学中的作用。 将Tff 2/IL-33途径鉴定为过敏反应的重要驱动器和放大器， 导致用于治疗过敏性疾病的疾病修饰疗法的发展。