Solitary chemosensory / tuft cells in lung regeneration and inflammation

肺再生和炎症中的孤立化学感应/簇细胞

• 批准号: 10171904
• 负责人: Andrew Vaughan
• 金额: $ 39.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171904
• 关键词: Ablation; Acetylcholine; Address; Adult; Affect; Asthma; Attenuated; Blood; Body Weight decreased; Brush Cell; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Childhood Asthma; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Cicatrix; Cre driver; Cytokeratin; Data; Development; Diphtheria Toxin; Disease; Distal; Effector Cell; Eicosanoids; Epithelial; Epithelial Cells; Etiology; Exhibits; Exposure to; Fibrosis; Frequencies; Gases; Genes; Genetic; Goblet Cells; Immunity; Individual; Infection; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Interleukin-13; Interstitial Lung Diseases; Intestines; Intraepithelial Neoplasia; Link; Lung; Lung Inflammation; Lung diseases; Lymphoid; Measures; Mediating; Metaplastic Cell; Modeling; Mus; Natural regeneration; Nippostrongylus; Organoids; Output; Paracrine Communication; Parasites; Pathogen detection; Pathologic; Pathology; Pathway interactions; Phenotype; Predisposition; Pulmonary Pathology; Pyroglyphidae; Resolution; Risk Factors; Signal Transduction; Testing; Time; Tissues; Viral; Viral Respiratory Tract Infection; airway hyperresponsiveness; asthmatic; base; chronic inflammatory lung disease; cytokine; diphtheria toxin receptor; eosinophil; epithelial repair; epithelial stem cell; helminth infection; immunopathology; influenza infection; injured; lung development; lung injury; lung regeneration; mucosal site; neutralizing antibody; overexpression; pathogen; preservation; prevent; pulmonary function; repaired; respiratory pathogen; response; small molecule; surfactant; therapeutic target; tissue regeneration; tissue repair; tool; transcription factor

Project Summary / Abstract Respiratory viral infections represent a major risk factor for the development of asthma. Moreover, severe influenza injury can result in ineffective repair and persistent loss of pulmonary function. The enduring changes caused by viral-induced lung injury that might explain chronic disease are not understood. We recently identified ectopic tuft / solitary chemosensory cells (SCCs) arising in the distal lung after H1N1 influenza infection. Since SCCs are increasingly recognized as critical orchestrators of both inflammation and epithelial tissue regeneration and remodeling, we posit that they are a likely driver of chronic lung pathology. This proposal will address the central hypothesis that inactivation / ablation of ectopic SCCs will promote the resolution of dysplastic remodeling and reduce chronic Th2-biased inflammatory disease, but may also increase susceptibility to pathogens controlled by Th2 responses following influenza infection. The major aims to address this hypothesis are to 1) ascertain the effects of SCC presence and specific SCC-derived signals on epithelial progenitor cells (fate and proliferation) during repair, and 2) determine whether the development of SCCs impacts Th2-mediated inflammatory disease (asthma) or parasitic protection. Completion of this project will validate SCCs as important drivers of pulmonary disease and will also facilitate identification of specific SCC effector pathways that could allow for preservation of host-protective benefits while attenuating their contribution to pathology.

项目总结/摘要 呼吸道病毒感染是哮喘发生的主要危险因素。 此外，严重的流感损伤可导致无效的修复和持续的损失。 肺功能病毒性肺损伤引起的持久变化， 可能解释慢性病的原因尚不清楚。我们最近发现了异位丛/ H1N1流感后肺远端出现孤立性化学感受细胞（SCC） 感染由于SCC越来越被认为是两者的关键协调， 炎症和上皮组织再生和重塑，我们认为他们是一个 可能是慢性肺部病变的诱因这项建议将解决中央 假设异位SCC的灭活/消融将促进消退 和减少慢性Th 2偏性炎症性疾病， 但也可能增加对由Th 2应答控制的病原体的易感性 流感感染后。解决这一假设的主要目的是1） 确定SCC的存在和特定SCC衍生信号对上皮细胞的影响， 祖细胞（命运和增殖），和2）确定是否 SCC的发展影响Th 2介导的炎性疾病（哮喘），或 寄生保护本项目的完成将验证SCC作为 肺疾病，也将有助于识别特定的SCC效应 这些途径可以允许在减弱宿主保护性益处的同时保留宿主保护性益处， 对病理学的贡献。