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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：
10218653
负责人：
TEAL S HALLSTRAND
金额：
$ 76.08万
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/10218653
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 Effector Cell Epithelial Epithelial Cells Exercise Gene Expression Genomic approach Goals House Dust Mite Allergens Immune response Individual Infiltration Inflammation Lead Link Location Mediating Mediator of activation protein Modeling Molecular Molecular Target Patients Phenotype Population 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 quantitative imaging receptor recruit 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.

项目总结