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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：
10853347
负责人：
Michelle Lynn Manni
金额：
$ 7.28万
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：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

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.

项目摘要过敏性哮喘影响全世界约3亿人。随着哮喘的发病率继续上升，因此，将免疫和病理生理机制与哮喘内型联系起来的研究非常重要以建立更有针对性和更有效的治疗方法。重度、类固醇不敏感（非嗜酸性粒细胞）哮喘占目前疾病负担的一半以上，但很少有研究关注这一点疾病亚群在严重难治性疾病中，过敏原特异性、类固醇不敏感性辅助性T细胞（Th）17和/或Th 2 细胞被认为是哮喘发病机制的关键，导致肺部炎症，粘液高分泌和气道高反应性。Th 17免疫细胞因子白细胞介素（IL）-22在免疫系统中起着至关重要的作用。维持上皮完整性和促进修复的作用。IL-22受体α-2（IL-22 Ra 2），一种可溶性 IL-22受体，抑制其活性。IL-22和内源性IL-22 Ra 2的意义，以及IL-22 Ra 2的表达。在严重哮喘中调节它们的途径尚不清楚。除了IL-22 Ra 2，I型干扰素（IFN），由IFNα亚型和IFNβ组成，是免疫调节剂，在某些情况下改变IL-10和IL-22信号传导。炎症性疾病背景。根据我们的初步和已发表的研究结果，我们假设IL- 22 Ra 2和I型IFN通过阻断IL-22信号传导而使严重过敏性气道疾病（AAD）永久化，这是减轻AAD和维持肺中上皮完整性所必需的。以下目标将研究这一假设：1）研究IL-22 Ra 2是否通过改变IL-22来调节重度AAD 2）确定I型IFN是否通过诱导IL-22 Ra 2和限制IL-22 Ra 2在肺中的生物利用度来促进严重AAD。肺中的IL-22活性，和3）检查肺上皮中的IL-22信号传导是否加重严重AAD 并维持肺中上皮的完整性。本申请中提出的工作将开创调查 IL-22 Ra 2和I型干扰素作为过敏性疾病调节因子的作用，并将揭示其潜在的 IL-22轴在AAD期间保护肺上皮的分子机制。这部小说在A 临床前动物模型和人类样本将揭示治疗严重的对标准疗法反应不佳的哮喘。