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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.

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