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

• 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
• 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

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.

项目概要/摘要 严重哮喘内型，涉及以 Th17 为主的中性粒细胞浸润气道 环境、过度气道重塑和对传统疗法的抵抗已经出现 在过去几年的患者中。在转录组筛选中，我们发现 TNF 超家族 成员 LIGHT，在模仿人类的严重哮喘小鼠模型中高度富集 除了在患者的痰液中富集之外，还与疾病有关。该提案将评估 LIGHT 信号传导在 1) 中性粒细胞中促进气道中性粒细胞增多，2) 基质细胞中的作用 促进病理重塑和类固醇抵抗，3）它将评估致病性 通过 LIGHT 与 Th2 细胞相比，Th17 细胞作为气道重塑驱动因素的作用 生产。此外，我们有证据表明 TNF 超家族 LIGHT 会减少气道 重塑并将讨论 LIGHT 封锁与中性粒细胞耗竭或 IL17 的比较 中和，减少 NA 症状：气道阻力、上皮损伤、成纤维细胞 激活和中性粒细胞募集。最后，该项目将解决组合是否 阻断光和类固醇治疗，可以消除严重哮喘的气道重塑， 我们建立了小鼠模型和人肺培养皿模型。