Origin and Function of Intra-epithelial Mast Cells in Asthma

哮喘上皮内肥大细胞的起源和功能

基本信息

批准号：
10599191
负责人：
TEAL S HALLSTRAND
金额：
$ 73.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599191
关键词：
3-Dimensional Address Air Allergens Allergic Asthma Cell physiology Cells Cellular biology Child Chymase Coculture Techniques Cross-Sectional Studies Development Disease Disease Progression Dryness Effector Cell Epithelial Cells Epithelium Exercise Gene Expression Genomic approach Goals House Dust Mite Allergens Immune response Individual Infiltration Inflammation Lead Link Location Mediating Mediator Modeling Molecular Molecular Target Osmosis Patients Phenotype Population Predisposition Pyroglyphidae Research Sampling Severities Source Submucosa Three-Dimensional Imaging airway epithelium airway hyperresponsiveness asthma model asthmatic airway cytokine design immunopathology in vivo in vivo Model intraepithelial lipid mediator mast cell mouse model novel peripheral blood prevent progenitor proliferation potential quantitative imaging receptor recruit respiratory examination respiratory imaging response stem cells

项目摘要

Project Summary Airway hyperresponsiveness (AHR) is a fundamental feature of asthma and is the hallmark of the disease in the majority of patients with asthma. Our lab has been working to understand the underlying immunopathogenesis of AHR and recently discovered using three-dimensional quantitative imaging of the airway wall that in asthma there is a shift in mast cells (MC)s from the submucosa to the airway epithelium that is closely related to the severity of AHR as well as features of type-2 (T2) inflammation. This shift is critical as we identified a IL-33 dependent feed-forward loop in which MCs regulate the expression of epithelial IL-33 (IL33), indicating that MCs serve not only as effector cells but also regulate T2 inflammation through IL-33. This feed-forward loop is accentuated in airway epithelial cells (AEC)s from individuals with asthma indicating that the unique microenvironment that is established by the epithelium in asthma is critical for the propagation of AHR and T2 inflammation through this feed-forward interaction between MCs and the airway epithelium. The major goals of this research are to identify the underlying basis for MC infiltration of the airway epithelium, the molecular details of this interaction between MCs and primary AECs from individuals with asthma and the in vivo relevance of the IL-33-MC-axis using selected murine models of asthma. Given that mature MCs arise from circulating progenitors, we hypothesize that the number of MC progenitors (MCP)s in the airways is increased in asthma, and these cells function in concert with the susceptible airway epithelium to orchestrate T2 inflammation. We will directly address our hypothesis by using airway samples and primary AECs from individuals with and without asthma and/or allergic sensitization, combined with AEC- MC coculture models, and murine models of asthma in which we examine the function of the IL-33-MC-axis. In specific aim 1, we investigate the differences in the number and proliferation potential of MCPs in the airways and peripheral blood of subjects with asthma and AHR, relative to non-asthmatic control subjects with and without allergic sensitization. We further examine the expansion of MCPs in the airways following allergen challenge in individuals with asthma. In specific aim 2, we determine how the asthmatic airway epithelium interacts with MCs to regulate T2 inflammation, using an ex vivo model of primary AECs from subjects with and without asthma to examine this feed-forward mechanism. In specific aim 3, we use selective IL-33 receptor deletion in MCs in an in vivo model to understand how IL-33 acts through MCs to regulate the development of T2 inflammation and AHR. The completion of these studies using airway samples, phenotyped AECs, and sophisticated murine models will move the field forward through a better understanding of the interplay between AECs and intraepithelial MCs that serve to regulate AHR and the T2 immune response.

项目概要气道高反应性 (AHR) 是哮喘的基本特征，也是该病的标志大多数哮喘患者。我们的实验室一直致力于了解底层 AHR 的免疫发病机制，最近使用三维定量成像发现气道壁，在哮喘中肥大细胞（MC）从粘膜下层转移到气道上皮，与 AHR 的严重程度以及 2 型（T2）炎症的特征密切相关。这种转变至关重要，因为我们发现了一个 IL-33 依赖的前馈环，其中 MC 调节上皮 IL-33 的表达 (IL-33)，表明 MC 不仅作为效应细胞，还通过 IL-33 调节 T2 炎症。这种前馈循环在哮喘患者的气道上皮细胞 (AEC) 中得到加强，表明哮喘上皮细胞建立的独特微环境对于哮喘的传播至关重要通过 MC 和气道上皮之间的前馈相互作用来控制 AHR 和 T2 炎症。本研究的主要目标是确定 MC 浸润气道的根本原因上皮细胞，MC 与个体原代 AEC 之间相互作用的分子细节使用选定的哮喘小鼠模型来研究哮喘和 IL-33-MC 轴的体内相关性。鉴于成熟的 MC 来自循环祖细胞，我们假设 MC 祖细胞的数量哮喘患者气道中的 (MCP) 会增加，这些细胞与易感气道协同发挥作用上皮细胞协调 T2 炎症。我们将通过使用气道样本直接解决我们的假设以及来自患有或不患有哮喘和/或过敏性过敏的个体的主要 AEC，并结合 AEC- MC 共培养模型和小鼠哮喘模型，我们在其中检查 IL-33-MC 轴的功能。在具体目标1，我们研究气道中MCP的数量和增殖潜力的差异患有哮喘和 AHR 的受试者的外周血和外周血，相对于患有和无过敏致敏作用。我们进一步检查了过敏原后 MCP 在气道中的扩展哮喘患者面临的挑战。在具体目标 2 中，我们确定哮喘气道上皮如何与 MC 相互作用以调节 T2 炎症，使用来自患有和没有哮喘来检查这种前馈机制。在具体目标3中，我们使用选择性IL-33受体在体内模型中删除 MC 来了解 IL-33 如何通过 MC 发挥作用来调节 T2 炎症和 AHR。使用气道样本、表型 AEC 和复杂的小鼠模型将通过更好地理解相互作用来推动该领域向前发展 AEC 和上皮内 MC 之间的作用，用于调节 AHR 和 T2 免疫反应。