Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection

通过靶向病毒感染后的簇细胞改善肺再生

• 批准号: 10471373
• 负责人: Jianwen Que
• 金额: $ 58.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471373
• 关键词: 2019-nCoV; Ablation; Acute Lung Injury; Address; Alternative Therapies; Alveolar; Alveolar Cell; Alveolus; Attenuated; Basal Cell; Brush Cell; COVID-19; COVID-19 pandemic; COVID-19 pandemic effects; COVID-19 patient; Cations; Cell Differentiation process; Cells; Chemosensitization; Chronic Disease; Clinical; Coronavirus; Data; Disease; Distal; Epithelial Cells; Exhibits; Fibrosis; Financial Hardship; Foundations; Genetic; Genetic Transcription; Goblet Cells; Health; Hyperplasia; Impairment; In Situ Hybridization; Infection; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Intestines; Knock-in Mouse; Ligands; Lung; Lung diseases; Mediating; Metaplasia; Modeling; Molecular; Mucous body substance; Mus; Natural regeneration; Organoids; Oxides; Pathway interactions; Peripheral; Persons; Pharmacologic Substance; Phase; Play; Reagent; Role; SARS-CoV-2 infection; Signal Transduction; Structure; Structure of parenchyma of lung; TRPM5 gene; Testing; Tissues; Virus; Virus Diseases; acute infection; alveolar epithelium; antagonist; cell type; cytokine; directed differentiation; efficacy testing; experimental study; flu; helminth infection; improved; influenza infection; insight; lung development; lung injury; lung regeneration; mortality; mouse model; notch protein; novel; novel strategies; novel therapeutic intervention; paracrine; receptor; regeneration function; repaired; seasonal influenza; single cell analysis; stem cells; targeted treatment; therapeutic target; triphenylphosphine

ABSTRACT Seasonal influenza and the current COVID-19 pandemic cause serious health and financial burdens. Severe viral infection leads to acute lung injury, inflammation and contributes to tissue remodeling and fibrosis. Intriguingly, clusters of ectopic basal cells (also known as pod cells) are present in the peripheral lungs during acute infection and remodeling phases. Initial studies indicated that these cells were able to generate type I and II alveolar epithelial cells (AECs). Nevertheless, subsequent lineage tracing studies revealed that pod cells had minimal if any contribution to alveolar regeneration. Moreover, our preliminary data suggest that pod cells give rise to goblet cells, resulting in mucous metaplasia accompanied by the presence of chemosensory tuft cells (also known as brush cells). Significantly, genetic ablation of tuft cells promotes the differentiation of pod cells into AECs. Our further analyses revealed that tuft cells express the Notch ligand Jag2, whereas pod cells express Notch receptors with prominent Notch activation. Consistently, Notch inhibition led to reduced mucous metaplasia and improved alveolar regeneration. We therefore hypothesize that tuft cells promote mucous metaplasia of pod cells and impede alveolar regeneration via paracrine JAG2/Notch activation upon viral infection. Two specific aims were devised to test the hypothesis. Aim1: To address the molecular mechanisms by which tuft cells promote mucous metaplasia following viral infection. Aim2: To promote the differentiation of pod cells into AECs through targeting JAG2 in tuft cells. In this aim we will combine a novel COVID-19 mouse model and pod cell organoids established from COVID-19 patient lungs to test the efficacy of a JAG/Notch decoy in promoting alveolar regeneration. Together this proposal will not only elucidate the disease mechanisms impairing lung regeneration post viral infection, but also offer new therapeutic approaches to treat lungs infected by influenza and coronavirus.

抽象的 季节性流感和当前的 COVID-19 大流行造成严重的健康和经济负担。严重病毒感染 导致急性肺损伤、炎症并促进组织重塑和纤维化。有趣的是，异位簇 基底细胞（也称为豆荚细胞）在急性感染和重塑阶段存在于周围肺中。最初的 研究表明这些细胞能够产生 I 型和 II 型肺泡上皮细胞 (AEC)。尽管如此， 随后的谱系追踪研究表明，豆荚细胞对肺泡再生的贡献即使有，也是微乎其微的。 此外，我们的初步数据表明豆荚细胞产生杯状细胞，导致粘液化生并伴有 通过化学感应簇细胞（也称为刷细胞）的存在。值得注意的是，簇细胞的基因消融促进了 豆荚细胞分化为 AEC。我们的进一步分析表明簇细胞表达Notch配体Jag2， 而豆荚细胞则表达具有显着Notch激活作用的Notch受体。一致地，Notch 抑制导致减少 粘液化生和改善的肺泡再生。因此，我们假设簇细胞促进粘液 荚细胞化生并通过病毒感染时旁分泌 JAG2/Notch 激活阻碍肺泡再生。 设计了两个具体目标来检验该假设。目标1：阐明簇细胞的分子机制 促进病毒感染后的粘膜化生。目的2：通过促进荚细胞分化为AEC 靶向簇细胞中的 JAG2。为此，我们将结合新型 COVID-19 小鼠模型和豆荚细胞类器官 从 COVID-19 患者肺部建立，以测试 JAG/Notch 诱饵在促进肺泡再生方面的功效。 该提案不仅将阐明病毒感染后损害肺再生的疾病机制，而且 还提供了治疗流感和冠状病毒感染肺部的新治疗方法。