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

基本信息

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
项目类别：
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

项目摘要

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.

过敏性疾病继续对现代化社会造成重大的公共卫生负担。虽然过敏性疾病的病因尚不清楚，人们认为它们是由于异常的 Th2 免疫而产生的遗传易感个体的反应。尽管有这样的认识，驱动 Th2 介导的因素免疫反应仍然难以捉摸。我们的初步数据表明了过敏原的新范式暴露会诱导上皮细胞损伤，从而导致上皮衍生因子三叶因子的释放 2. Tff2 反过来诱导“警报素”IL-33 的释放，从而驱动先天性 Th2 细胞因子的产生免疫细胞。 Th2 细胞因子的产生通过驱动额外的反应来放大和维持反应 Tff2 发布。重要的是，我们发现哮喘儿童的上皮细胞中 TFF2 水平升高与健康对照组的细胞相比，这些细胞经历了急性发作。因此，该提案的目标是测试新的假设，即 TFF2 的异常上皮细胞产生在诱导和 Th2 介导的过敏反应以 IL-33 依赖性方式表达。此外，我们建议控制该途径的基因（TFF2、IL-33、IL-1RL1）的遗传变异会增加以下风险：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）孩子们。为了检验这一假设，我们提出以下具体目标：1）确定 Tff2/IL-33 通路启动 Th2 介导的过敏性气道反应； 2）确定 TFF2介导IL-13依赖性AHR和粘液细胞化生的机制； 3) 确定 TFF2/IL-33 通路失调是否会增加患过敏性疾病的风险从辛辛那提地区招募的儿童群体。该项目的研究与受益于 U19 项目 1 和 2 中产生的资源和信息，这些资源和信息也重点关注确定粘膜上皮功能改变在过敏性疾病病因学中的作用。 Tff2/IL-33 通路作为过敏反应的重要驱动因素和放大器的鉴定应该导致了治疗过敏性疾病的疾病修饰疗法的发展。