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

基本信息

批准号：
10298186
负责人：
Jianwen Que
金额：
$ 63.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10298186
关键词：
2019-nCoV Ablation Acute Lung Injury Address Affect Alternative Therapies Alveolar Alveolar Cell Alveolus Attenuated Basal Cell Brush Cell COVID-19 COVID-19 pandemic 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 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 cell type cytokine 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

项目摘要

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目前的Covid-19大流行造成了严重的健康和经济负担。严重的病毒感染导致急性肺损伤，炎症，并导致组织重塑和纤维化。有趣的是，异位簇在急性感染和重塑阶段，基底细胞（也称为POD细胞）存在于外周肺中。最初的研究表明，这些细胞能够生成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，如果对肺泡再生有任何贡献，POD细胞的含量很小。此外，我们的初步数据表明，POD细胞会产生杯状细胞，从而导致粘液上流如鼻。通过化学感应簇细胞（也称为刷细胞）的存在。值得注意的是，簇细胞的遗传消融促进 POD细胞分化为AEC。我们的进一步分析表明，簇细胞表达了Notch配体JAG2，而POD细胞表达具有突出缺口激活的Notch受体。一致地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 POD细胞的化生和病毒感染后通过旁分泌Jag2/Notch激活阻碍肺泡再生。设计了两个具体的目标来检验该假设。 AIM1：解决簇细胞的分子机制病毒感染后促进粘液化生。 AIM2：通过靶向簇细胞中的JAG2。在此目的中，我们将结合一种新型的Covid-19小鼠模型和POD细胞器官从COVID-19患者肺建立，以测试JAG/Notch诱饵在促进肺泡再生方面的功效。该提案在一起不仅会阐明病毒感染后疾病机制损害肺部再生，而且还会削弱还提供新的治疗方法来治疗受流感和冠状病毒感染的肺部。