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.

项目摘要/摘要 一种以Th17为主的中性粒细胞渗入呼吸道的严重哮喘内型 环境，过度的呼吸道重塑和对传统治疗的抵抗已经出现。 在过去的几年里。在转录水平筛选中，我们发现了肿瘤坏死因子超家族 LIGH成员在模拟人类严重哮喘的小鼠模型中高度浓缩 疾病，除了在患者的痰中浓缩外。这项提案将评估 光信号在1)中性粒细胞促进气道中性粒细胞增多中的作用，2)基质细胞 促进病理重塑和类固醇抵抗，以及3)它将评估致病因素 与Th2细胞相比，Th17细胞在气道重塑中的作用 制作。此外，我们有证据表明，肿瘤坏死因子超家族灯减少了呼吸道 重塑，并将解决光阻断与中性粒细胞耗竭或IL17相比的问题 中和，在减少NA症状：呼吸道阻力，上皮损伤，成纤维细胞 激活和中性粒细胞募集。最后，这个项目将解决是否组合 阻断轻度和类固醇治疗，可以消除重症哮喘患者的气道重塑 我们建立了小鼠模型和人类盘中肺脏模型。