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.

项目总结/摘要 一种涉及中性粒细胞浸润气道并以Th 17为主的严重哮喘内源性 环境，过度气道重塑和对常规治疗的抵抗， 在过去的几年里，患者。在转录组筛选中，我们发现TNF超家族 成员LIGHT在模拟人的严重哮喘小鼠模型中高度富集， 疾病，除了在病人的痰中富集。该提案将评估 LIGHT信号在1）嗜中性粒细胞促进气道嗜中性粒细胞，2）基质细胞中的作用 促进病理性重塑和类固醇抵抗，和3）它将评估致病性 通过LIGHT，与Th 2细胞相比，Th 17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减少气道炎症， 重塑，并将解决如何轻封锁相比，嗜中性白细胞耗竭，或IL 17 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，本项目将讨论是否组合 阻断LIGHT和类固醇治疗，可以消除严重哮喘的气道重塑， 建立了小鼠肺移植模型和人肺移植模型。