Immune Airway-Epithelial Interactions in Steroid-Refractory Severe Asthma

类固醇难治性严重哮喘中的免疫气道-上皮相互作用

基本信息

批准号：
10625494
负责人：
Anuradha Ray
金额：
$ 186.86万
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：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625494
关键词：
Address Adrenal Cortex Hormones Air Animal Model Anti-Inflammatory Agents Apoptosis Asthma Bioinformatics Biological Biological Markers Biological Products Bronchoalveolar Lavage CD8-Positive T-Lymphocytes CXCL10 gene Cell Culture System Cell Death Cell Separation Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Characteristics Chemotactic Factors Collecting Cell Communication Complex Computer Analysis Cytometry Data Development Disease Disease model Epigenetic Process Epithelial Cells Epithelium Failure Functional disorder Gene Expression Profiling Genetic Glucocorticoid Receptor Guidelines Heterogeneity Human IL18 gene Immune Immune System Diseases Immune response Immunologics Immunosuppression In Vitro Inflammation Inflammatory Inhalation Innate Immune Response Interferon Type II Interferons Interleukin-4 Knowledge Laboratories Liquid substance Lymphocyte Memory Molecular Molecular Target Morbidity - disease rate Mucins Natural Immunity Pathogenesis Pathway interactions Patients Peptide Hydrolases Phenotype Process Production Publishing Quality of life Refractory Regulation Research Risk Role STAT1 gene Sampling Signal Transduction Statistical Data Interpretation Steroid Resistance Steroids Stimulus Subgroup Symptoms T cell receptor repertoire sequencing T-Lymphocyte Techniques Time Tissues adaptive immune response adaptive immunity airway epithelium asthmatic asthmatic patient bronchial epithelium clinical diagnosis cost disorder control experience interest molecular phenotype mouse model multiple omics new therapeutic target novel novel therapeutics programs pulmonary function repaired response side effect targeted treatment trait transcriptome sequencing treatment response

项目摘要

Severe asthma (SA) is complex, multifactorial and refractory to treatment by corticosteroids (CS). In recent years, some progress has been made in its treatment with the advent of biologics. However, despite these advancements, there still remain challenges in the treatment of these patients because of an incomplete understanding of the dysfunction of immune and epithelial cells, which underlies this disease. This is further complicated by the poor biomarkers available to differentiate disease for targeted therapy, and amplified by their enormous costs, particularly when prescribed imprecisely. Progress made in Project 1 in the current cycle using mass cytometry/CyTOF, show clustering of SA patients into 2 groups displaying distinct immune profiles divided along the lines of innate and adaptive immunity. Progress made in Project 2 in studies of bronchial epithelial cells (BECs) in SA suggest the presence of two fundamentally different molecular phenotypes. The BECs in one group primarily respond to inhaled environmental stimuli to drive an innate intrinsic phenotype. In the second group, BEC cell death pathways intersect with CD8 T-cell immune processes to drive an immune interactive phenotype. Taken together, these findings prompted us to hypothesize that two distinct immune mechanisms, one regulated by innate immune cells, and the second by T cells, are critical determinants of SA. Interactions between airway epithelial cells in the context of genetic/epigenetic risks and immune cells together with induction of cellular death contribute to two SA phenotypes. This hypothesis will be addressed in the following two highly interactive projects: Project 1 will use human samples and mouse models of disease to: a) characterize the CITE-seq and TCR-seq airway immune cells collected by BAL and investigate the impact of dupilumab on immune phenotype, b) study the importance of FceRI-expressing innate immune cells and IL-7Ra signaling in FceRI+ cells in promoting a SA phenotype using a novel protease-based mouse model, and c) study mechanisms underlying regulation of TRM cell phenotype and impact on disease using a T cell-driven mouse model of SA. Project 2 will use fresh and cultured healthy and asthmatic BECs to: a) determine the mechanisms for and functional implications of an innate intrinsic epithelial phenotype, b) evaluate the role of GSDMB in the development of a CD8 T-cell immune interactive phenotype and its functional implications, and c) Integrate immune-inflammatory phenotypes with epithelial molecular phenotypes ex vivo and in vitro. Synergistic interactions among projects will be afforded by support from: Core A, the Administrative Core, to coordinate the activities of the Program Project at all levels, Core B, the Human Biological Sampling and Immunocytometry Core and Core C, the RNA-Seq and Bioinformatics Core. Taken together, these projects will establish new concepts in immune- epithelial interactions underlying asthma pathogenesis and identify novel targets for therapy.

严重的哮喘（SA）是复杂的，多因素和对皮质类固醇（CS）治疗的难治性的。最近多年来，随着生物制剂的出现，在治疗中取得了一些进展。但是，尽管如此进步，由于不完整，这些患者的治疗仍然存在挑战对这种疾病的基础的免疫和上皮细胞功能障碍的理解。这是进一步的由于可用于区分靶向治疗的疾病的生物标志物的不良生物标志物使它们的巨大成本，尤其是在不符合规定的情况下。当前项目1中的进度使用质量细胞术/细胞循环，显示SA患者聚集成2组，显示出不同的免疫力曲线沿着先天和适应性免疫的线路分裂。项目2在研究中取得的进展 SA中的支气管上皮细胞（BEC）表明存在两个根本不同的分子表型。一个组中的BEC主要响应吸入的环境刺激以推动先天固有表型。在第二组中，BEC细胞死亡途径与CD8 T细胞免疫相交驱动免疫互动表型的过程。综上所述，这些发现促使我们假设两种不同的免疫机制，一种由先天免疫细胞调节，第二个由T 细胞是SA的关键决定因素。气道上皮细胞之间的相互作用遗传/表观遗传风险和免疫细胞以及诱导细胞死亡有助于两个SA 表型。该假设将在以下两个高度互动的项目中解决：项目1将使用人类样品和疾病的小鼠模型：通过BAL收集的免疫细胞并研究了杜皮鲁姆单抗对免疫表型的影响，b）研究在促进Sa中表达FCERI的先天免疫细胞和IL-7RA信号的重要性使用基于蛋白酶的新型小鼠模型的表型，以及c）研究机制的研究机制 TRM细胞表型和使用T细胞驱动的小鼠模型对疾病的影响。项目2将使用新鲜并进行培养的健康和哮喘的BEC：a）确定的机制和功能含义先天的内在上皮表型，b）评估GSDMB在CD8 T细胞发展中的作用免疫互动表型及其功能含义，c）整合免疫炎症具有上皮分子表型的表型离体和体外。项目之间的协同互动将得到以下支持：行政核心核心A的支持，以协调该计划的活动在各个级别的项目中，核心B，人类生物学采样和免疫细胞仪核心和核心C， RNA-seq和生物信息学核心。综上所述，这些项目将在免疫中建立新的概念哮喘发病机理的基础上皮相互作用并确定治疗的新靶标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Integrative analysis of spatial transcriptome with single-cell transcriptome and single-cell epigenome in mouse lungs after immunization.

DOI：
10.1016/j.isci.2022.104900
发表时间：
2022-09-16
期刊：
ISCIENCE
影响因子：
5.8
作者：
Xu, Zhongli;Wang, Xinjun;Fan, Li;Wang, Fujing;Lin, Becky;Wang, Jiebiao;Trevejo-Nunez, Giraldina;Chen, Wei;Chen, Kong
通讯作者：
Chen, Kong

Digital Imaging Analysis Reveals Reduced Alveolar α-Smooth Muscle Actin Expression in Severe Asthma.

DOI：
10.1097/pai.0000000000000926
发表时间：
2021-08-01
期刊：
Applied immunohistochemistry & molecular morphology : AIMM
影响因子：
0
作者：
Jerome JA;Wenzel SE;Trejo Bittar HE
通讯作者：
Trejo Bittar HE

15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.

DOI：
10.1172/jci151685
发表时间：
2022-01-04
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Nagasaki T;Schuyler AJ;Zhao J;Samovich SN;Yamada K;Deng Y;Ginebaugh SP;Christenson SA;Woodruff PG;Fahy JV;Trudeau JB;Stoyanovsky D;Ray A;Tyurina YY;Kagan VE;Wenzel SE
通讯作者：
Wenzel SE

Predicting atopic asthma by using eNose breath profiles with machine learning.

通过使用电子鼻呼吸曲线和机器学习来预测特应性哮喘。