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Epithelial regulation of ECM and leukocyte adhesion in viral-triggered asthma

病毒引发的哮喘中 ECM 和白细胞粘附的上皮调节

基本信息

批准号：
10202414
负责人：
Steven F Ziegler
金额：
$ 43.24万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
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：
2020-05-14 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202414
关键词：
2019-nCoV Adhesions Adult Air Allergens Antigens Area Asthma Autopsy Binding COVID-19 Cell Differentiation process Cells Child Coculture Techniques Data Dermatophagoides Antigens Development Dictyoptera Disease Down-Regulation Environment Epithelial Epithelial Cells Epithelium Exposure to Extracellular Matrix Fibroblasts Functional disorder Genes Human Hyaluronan Immune Immune response Individual Infection Infectious Agent Infiltration Inflammation Inflammatory Investigation Lead Leukocytes Link Liquid substance Lung Myofibroblast Pathway interactions Phenotype Play Process Production Proteins Pyroglyphidae Regulation Resources Respiratory syncytial virus Rhinovirus Role Signal Transduction Smooth Muscle Actin Staining Method Specimen Structure System TSLP gene Testing Therapeutic Transforming Growth Factor beta Viral Viral Antigens Virus Diseases Virus Replication airborne allergen airway epithelium airway hyperresponsiveness airway remodeling asthma exacerbation asthmatic asthmatic airway base cytokine differential expression immunoregulation in vivo leukocyte activation mouse model programs recruit respiratory infection virus respiratory virus response versican

项目摘要

Project Summary The overarching hypothesis of this Program is that the airway epithelium serves as a central coordinator of the responses to respiratory virus infection, and that sensitization to aeroallergens and intrinsic differences in airway epithelial cells (AECs) between asthmatic and healthy individuals is the critical link between exposure and the development of dysfunctional airway responses in asthma. In Project 1, we will investigate the role of AEC-derived TGFβ in regulating airway ECM composition, including regulation of VCAN and HA accumulation and their degradation products in the airway ECM leading to increased adhesion and activation of inflammatory leukocytes. Based upon observations by our group and others, and additional preliminary data presented in Project 1, we hypothesize that viral infection with RSV or HRV, and allergen exposure with the common aeroallergens cockroach antigen (CRA) or house dust mite (HDM), of AECs from asthmatic as compared to healthy children induce human lung fibroblasts (HLFs) to produce an airway ECM enriched with VCAN, HA and their degradation products, leading to increased adhesion and activation of inflammatory leukocytes. We will test this global hypothesis and investigate mechanisms responsible for airway matrix dysregulation in asthma, and the resulting increased adhesion and activation of leukocytes. Using human asthmatic AEC and AEC/HLF co-cultures we will determine the effects of viral infection and aeroallergen exposure with CRA and HDM, on asthmatic AEC regulation of HLF ECM production and composition. Furthermore, we will determine the effects of asthmatic AEC infection by respiratory viruses and exposure to CRA or HDM antigen on leukocyte adhesion to and activation by ECM produced by HLF. Finally, using a murine model of viral-triggered asthma we will determine the role of epithelium in regulating cellular responses during viral infection and exacerbation.

项目摘要该计划的首要假设是气道上皮细胞作为呼吸道上皮细胞的中心协调者，对呼吸道病毒感染的反应，以及对空气过敏原的致敏性和哮喘患者和健康人之间的气道上皮细胞（AEC）是暴露之间的关键联系以及哮喘中气道功能障碍反应的发展。在项目1中，我们将研究 AEC衍生的TGFβ调节气道ECM组成，包括VCAN和HA积累的调节以及它们在气道ECM中的降解产物，导致炎性细胞粘附和活化增加，白细胞根据我们小组和其他人的观察，以及项目1，我们假设RSV或HRV的病毒感染，以及常见的过敏原暴露，与哮喘患者的AEC相比，健康儿童诱导人肺成纤维细胞（HLF）产生富含VCAN、HA和它们的降解产物，导致炎性白细胞的粘附和活化增加。我们将检验这一总体假设并研究哮喘气道基质失调的机制，以及由此导致的白细胞粘附和活化的增加。使用人哮喘AEC和AEC/HLF 共培养，我们将确定病毒感染和空气过敏原暴露与CRA和HDM的影响，哮喘AEC对HLF ECM产生和组成的调节。此外，我们将确定呼吸道病毒感染哮喘AEC及接触CRA或HDM抗原对白细胞粘附的影响并被HLF产生的ECM激活。最后，使用病毒引发哮喘的小鼠模型，我们将确定上皮细胞在病毒感染和恶化期间调节细胞反应的作用。