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The TNF Superfamily Control of Pathological Remodeling Associated with Severe Asthma

TNF超家族对严重哮喘相关病理重塑的控制

基本信息

批准号：
10710727
负责人：
Rana Elias Herro
金额：
$ 50.86万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710727
关键词：
Actins Address Airway Disease Airway Fibrosis Airway Resistance Allergens Area Asthma Automobile Driving B-Lymphocytes CSF2 gene CXCL2 gene Cells Chemotactic Factors Chemotaxis Chronic Coculture Techniques Collagen Data Deposition Development Epithelial Cells Epithelium Exhibits Extracellular Matrix Proteins Fibroblasts Genes Goals Heterogeneity Human IL17 gene Individual Inflammation Inflammation Mediators Inflammatory Knowledge Leukocytes Light Lung Mediating Mediator Migration Assay Modeling Mus Names Neutrophil Infiltration Neutrophilia Onset of illness Organoids Outcome Pathogenesis Pathogenicity Pathologic Patients Phenotype Predisposition Production Proliferating Refractory Disease Resistance Resistance development Role Severities Signal Transduction Smooth Muscle Source Sputum Standardization Steroid Resistance Steroids Stromal Cells Symptoms T-Cell Activation T-Lymphocyte TNF gene Testing Th2 Cells Therapeutic Intervention Time Transforming Growth Factor beta Up-Regulation Work airway inflammation airway remodeling asthma model asthmatic asthmatic patient cell type combinatorial comparative efficacy conventional therapy eosinophilic asthma epithelial to mesenchymal transition experimental study gain of function high risk human data human disease idiopathic pulmonary fibrosis member mortality mortality risk mouse model muscle hypertrophy neutrophil novel novel therapeutics receptor therapy resistant transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT A severe asthma endotype involving neutrophils infiltrating the airways with a Th17 dominant milieu, and excessive airway remodeling and resistance to conventional therapies, has emerged in patients in the past years. In a transcriptomic screen, we found that the TNF Superfamily member LIGHT, was highly enriched in a murine model of severe asthma mimicking the human disease, in addition to being enriched in the sputum of patients. This proposal will evaluate the contribution of LIGHT signaling in 1) neutrophils to promote airway neutrophilia, 2) stromal cells to promote pathological remodeling and steroid resistance, and 3) it will evaluate the pathogenic role of Th17 cells as drivers of airway remodeling compared to Th2 cells, through LIGHT production. Furthermore, we have evidence that the TNF Superfamily LIGHT decreases airway remodeling and will address how LIGHT blockade compares to neutrophilic depletion, or IL17 neutralization, in decreasing NA symptoms: airway resistance, epithelial damage, fibroblasts activation, and neutrophil recruitment. Lastly, this project will address whether the combinatorial blockade of LIGHT and steroid treatment, can abrogate airway remodeling in severe asthma, in the mouse model and the human lung-in-a-dish model we established.

项目总结/文摘