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Immune Mediators of IL-22 Signaling Alter Allergic Airway Disease

IL-22 信号的免疫介质改变过敏性气道疾病

基本信息

批准号：
9883286
负责人：
Michelle Lynn Manni
金额：
$ 41.36万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9883286
关键词：
Affect Allergens Allergic Disease Alveolar Macrophages Animal Model Antibodies Antiinflammatory Effect Asthma Attenuated Binding Binding Proteins Biological Availability Biological Response Modifiers Bone Marrow Cells Chronic Data Dendritic Cells Development Disease Disease model Drug resistance Epithelial Epithelial Cells Epithelium Extrinsic asthma Flow Cytometry Genes Goals Health Healthcare Systems Hematopoietic Human IFNAR1 gene Immune Immune response Immunomodulators Incidence Inflammation Inflammatory Injury Interferon Type I Interferon-alpha Interferons Interleukin Receptor Interleukin-10 Interleukins Investigation Ligands Link Lung Lymphoid Cell Modeling Molecular Mucous body substance Mus Myelogenous Ovalbumin Pathogenesis Pathway interactions Play Public Health Publishing Pulmonary Inflammation Pyroglyphidae Refractory Disease Reporter Role STAT1 gene STAT2 gene STAT3 gene Sampling Serum Severity of illness Signal Transduction Source Sputum Steroid Resistance Steroids Subgroup Surface Testing Th2 Cells Tissues United States Wild Type Mouse Work airway epithelium airway hyperresponsiveness allergic airway disease asthmatic asthmatic patient base bronchial epithelium burden of illness cytokine effective therapy improved in vivo insight interleukin-22 mucus hypersecretion new therapeutic target novel novel therapeutic intervention overexpression personalized medicine pre-clinical protein expression receptor repaired response targeted treatment

项目摘要

PROJECT SUMMARY Allergic asthma affects approximately 300 million people worldwide. As the incidence of asthma continues to rise, studies linking immune and pathophysiologic mechanisms to asthma endotypes are of great importance to establish more targeted and effective therapies. Severe, steroid-insensitive (non-eosinophilic) asthma accounts for greater than half the current disease burden, but few studies have focused on modeling this disease subset. In severe refractory disease, allergen-specific, steroid-insensitive T helper (Th) 17 and/or Th2 cells are thought to critically orchestrate asthma pathogenesis, resulting in pulmonary inflammation, mucus hypersecretion, and airway hyperresponsiveness. The Th17 immune cytokine interleukin (IL)-22 plays a vital role in maintaining epithelial integrity and promoting repair. IL-22 receptor alpha-2 (IL-22Ra2), a soluble receptor for IL-22, inhibits its activity. The significance of IL-22 and endogenous IL-22Ra2, as well as the pathways that regulate them in severe asthma, are unknown. Aside from IL-22Ra2, type I interferons (IFN), consisting of IFNα subtypes and IFNβ, are immunomodulators that alter IL-10 and IL-22 signaling in certain inflammatory disease contexts. Based on our preliminary and published findings, we hypothesize that IL- 22Ra2 and type I IFNs perpetuate severe allergic airway disease (AAD) by blocking IL-22 signaling, which is necessary to alleviate AAD and maintain epithelial integrity in the lung. The following aims will investigate this hypothesis: 1) Investigate whether IL-22Ra2 modulates severe AAD by altering IL-22 bioavailability in the lung, 2) Determine if type I IFNs promote severe AAD by inducing IL-22Ra2 and limiting IL-22 activity in the lung, and 3) Examine if IL-22 signaling in the epithelium of the lung alleviates severe AAD and maintains epithelial integrity in the lung. The proposed work in this application will pioneer investigations into the role of IL-22Ra2 and type I interferons as regulators of allergic disease and will uncover the potential molecular mechanisms by which the IL-22 axis protects the lung epithelium during AAD. This novel work in a preclinical animal model and human samples will uncover new therapeutic targets for the treatment of severe asthma that is poorly responsive to standard therapies.

项目总结