Epithelial cell reprogramming and mucus gel pathology in self-sustaining type 2 airway niches in asthma

哮喘自我维持型 2 型气道微环境中的上皮细胞重编程和粘液凝胶病理学

基本信息

批准号：
10472542
负责人：
John V Fahy
金额：
$ 56.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472542
关键词：
ATAC-seq Acids Alternative Splicing Anions Apical Area Asthma Basophils Biology Bronchoscopy Brush Cell CRISPR/Cas technology Cells Chromatin Chronic Cytokine Gene Cytokine Receptors Cytometry Development Disease Disulfides Elasticity Eosinophilia Epigenetic Process Epithelial Epithelial Cells Functional disorder Gel Gene Expression Gene Silencing Genes Genetic Polymorphism Genetic Transcription Goals Heterogeneity Human Human Resources Hydrogen Peroxide IL18 gene IL1R1 gene Immune Immunophenotyping Individual Inflammation Interleukin-1 beta Interleukin-13 Knowledge Lead Legal patent Ligands Lung Lung CAT Scan Mediator of activation protein Methods Methylation Mucins Mucous body substance Nature Outcome Measure Oxidation-Reduction Oxides Pathologic Pathology Pathway interactions Patients Plug-in Production Property Proteins Role Sampling Signal Transduction Sputum TSLP gene Thiocyanates Tissues Transcript Up-Regulation X-Ray Computed Tomography airway epithelium asthmatic asthmatic airway biophysical properties cell type chromatin remodeling curative treatments cytokine eosinophil eosinophil peroxidase experimental study human subject inhibitor injured airway knock-down lung imaging mast cell novel oxidation prevent receptor receptor expression single cell sequencing single-cell RNA sequencing small molecule treatment strategy virtual whole genome

项目摘要

Project Summary / Abstract Type 2 inflammation is initiated at the airway epithelium through the release of master cytokines such as IL-33 that drive type 2 cytokine production, eosinophilia, and mucus pathology. Tyope 2 inflammation becomes persistent when homeostatic mechanisms that normally contain it fail causing persistent disease. We find that lung imaging (computed tomography) frequently reveals mucus plugging in asthmatic airways and that the plugs are highly eosinophilic and persist for many years. These findings lead us to propose that airway injury leads to reprogramming of the epithelium to cause focal areas of type 2 inflammation and mucus plugging (“type 2 airway niches”). We have three Aims to characterize the biology of type 2 niches in asthma with an emphasis on reprogramming of immune cells and epithelial cells and on IL-13 driven mechanisms of mucus plug formation. AIM 1 will characterize the subtypes of immune cell, their receptor expression, and their niche specific gene expression. We will use mass cytometry (CyTOF) to enumerate type 2 cytokine producing cells and their receptor expression repertoire. AIM 2 will character epithelial cells in the niche using bulk and single cells sequencing and also methods to uncover niche-specific epigenetic changes in these cells with a focus on genes that regulate type 2 cytokines (IL-33, TSLP, IL25, IL1β). ATAC-seq and whole genome methylation studies will be included to characterize epigenetic changes in epithelial cells from plugged and non-plugged airways. AIM 3 will explore how cross-talk between epithelial cells and eosinophils results in mucus plug formation in the type 2 airway niche. Emphasis in this aim will be placed on IL-13 regulated pathways that caused epithelial cells to upregulate transport of redox-relevant halides such as thiocyanate and to increase section of mucin-like molecules such as FcγBP. To achieve its three aims, Project 3 will interact closely with projects 1 and 2, and it will take advantage of all cores, especially the resources of the human subjects core and the analytic capabilities of Core C. Our project will advance knowledge of the type 2 niche in ways that could point to novel treatment strategies to switch off type 2 inflammation and fundamentally modify asthma.

项目摘要 /摘要 2型炎症是通过释放主细胞因子（例如IL-33）在气道上皮开始的那种驱动2型细胞因子产生，嗜酸性粒细胞和粘液病理学。 2型炎症变成当通常包含其失败导致持续性疾病的稳态机制时，持续存在。我们发现肺成像（计算机断层扫描）经常揭示粘液插入哮喘气道，并且插头高度嗜酸性粒细胞并持续多年。这些发现使我们提出气道伤害导致重新编程上皮引起2型注射和粘液塞的焦点区域（2型气道）。）。我们有三个旨在表征哮喘中2型生物学的生物学，重点是对免疫细胞和上皮细胞的重编程以及粘液塞形成的IL-13驱动机制。 AIM 1将表征免疫细胞的亚型，其受体表达和其特异性基因表达。我们将使用质量细胞仪（Cytof）列举2型细胞因子产生细胞及其接收器表达曲目。 AIM 2将使用批量和单细胞进行测序在利基市场中的上皮细胞以及在这些细胞中发现利基特异性表观遗传变化的方法，重点是调节基因 2型细胞因子（IL-33，TSLP，IL25，IL1β）。将包括ATAC-SEQ和整个基因组甲基化研究为了表征来自堵塞和非拔掉气道的上皮细胞的表观遗传变化。 AIM 3将探索上皮细胞和嗜酸性粒细胞之间的串扰如何导致2型气道中的粘液塞形成利基。该目标的重点将放在IL-13受调节的途径上，导致上皮细胞更新与氧化还原相关的卤化物（例如硫氰酸酯）的运输，并增加粘蛋白样分子的截面，例如 FcγBP。为了实现其三个目标，项目3将与项目1和2紧密相互作用，它将利用优势在所有核心，尤其是人类受试者核心的资源和核心C的分析能力中项目将以可能指出新的治疗策略的方式来提高对2型利基市场的了解未接收2型注射，从根本上修改哮喘。