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Quercetin prevent airway epithelial remodeling and promote lung health in OPD

槲皮素可预防 OPD 患者气道上皮重塑并促进肺部健康

基本信息

批准号：
10633252
负责人：
Umadevi Sivanappa Sajjan
金额：
$ 45.13万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633252
关键词：
Acceleration Affect Airway Disease Anti-Inflammatory Agents Antioxidants Basal Cell Basal Cell Hyperplasia CDH1 gene Cell Cycle Cell Differentiation process Cell Proliferation Cells Chronic Obstructive Pulmonary Disease Consumption Cultured Cells Data Development Diet Epithelial Cells Epithelium Functional Regeneration Genes Goblet Cells HOX protein Health Benefit Homeobox Genes Homeostasis Human Immune response Infection Injury Innate Immune Response Knockout Mice Lung Lung diseases Maintenance Metaplasia Molecular Morphogenesis Mus Natural Immunity Natural regeneration Outcome Pathologic Pathway interactions Patients Placebos Play Property Publishing Pulmonary Inflammation Quercetin Regenerative pathway Regulation Repression Research Respiratory Tract Infections Rhinovirus Rhinovirus infection Role STC2 gene Signal Transduction Site Squamous Cell Testing Tissues adaptive immune response adaptive immunity airway epithelium airway immune response airway regeneration airway remodeling airway repair bronchial epithelium chemokine cytokine disease phenotype epithelial repair epithelium regeneration improved insight knock-down lung health mouse model non-smoker novel polarized cell polyphenol prevent programs pulmonary function repaired response stem cells transcriptional reprogramming transcriptomics

项目摘要

PROJECT SUMMARY Patients with chronic obstructive pulmonary disease often show airway epithelial remodeling including basal cell hyperplasia, and goblet cell and squamous cell metaplasia. Such pathologic changes profoundly affect the outcome of respiratory infection as airway epithelium plays a crucial role in defining the innate and adaptive immunity in the lungs. Airway basal cells are the specialized stem cells and regenerate functional mucociliary- differentiated airway epithelium upon injury. The fact that COPD patients show airway epithelial remodeling indicate dysregulated repair mechanisms in airway basal cells. Our research suggests that quercetin, a natural polyphenol reverses airway epithelial remodeling in a mouse model of COPD. Our preliminary studies indicate that quercetin reprograms dysregulated repair pathways in COPD basal cells leading to regeneration of normal airway epithelium. We conducted transcriptomic analysis of airway basal cells from healthy non-smokers and COPD subjects and COPD basal cells treated with quercetin. Results from this microarray indicated dysregulation of genes involved in tissue development and epithelial differentiation in COPD cells. Intriguingly, the topmost differentially regulated genes in both these pathways are genes involved in lung morphogenesis HOXA1 and HOXB2. In normal basal cells, HOXA1 is highly expressed in basal cells, while HOXB2 expression increased at two weeks of culturing and correlated with polarization of cells, a prerequisite step in differentiation. COPD basal cells showed significantly reduced expression of both HOXA1 and HOXB2 and quercetin treatment increased expression of both genes. Based on these observations, we will examine a novel hypotheses that quercetin via modulation of HOXA1 and HOXB2 corrects the dysregulated repair mechanisms, thus improving immune responses to respiratory infections and lung function in COPD. In Specific Aim 1, we will determine the role of HOXA1 and HOXB2 in the regeneration of airway epithelium, and whether quercetin corrects the dysregulated repair mechanism in COPD by modulation of these HOX genes. In Specific Aim 2, we will examine the molecular mechanisms by which quercetin-induced HOXA1 and HOXB2 participates in the regeneration of airway epithelium. In Specific Aim 3, we will examine whether quercetin-induced HOXA1 and HOXB2 participate in limiting exaggerated innate immune responses to rhinovirus infection and prevent progression of lung disease in COPD. Finally, we will confirm whether quercetin treatment reduces airway epithelial remodeling in COPD patients and correlate with the expression of HOXA1 and HOXB2. Completion of these studies will provide important insight into airway epithelial regeneration and the mechanisms by which quercetin reduces airway epithelial remodeling in COPD.

项目概要慢性阻塞性肺疾病患者经常表现出气道上皮重塑，包括基底细胞增生、杯状细胞和鳞状细胞化生。这种病理变化深刻地影响着呼吸道感染的结果，因为气道上皮在定义先天性和适应性方面起着至关重要的作用肺部的免疫力。气道基底细胞是专门的干细胞，可再生功能性粘膜纤毛- 损伤后气道上皮发生分化。 COPD 患者表现出气道上皮重塑的事实表明气道基底细胞的修复机制失调。我们的研究表明槲皮素是一种天然的多酚可逆转 COPD 小鼠模型中的气道上皮重塑。我们的初步研究表明槲皮素重新编程 COPD 基底细胞中失调的修复途径，从而导致正常细胞的再生气道上皮。我们对健康非吸烟者的气道基底细胞进行了转录组分析，慢性阻塞性肺病受试者和用槲皮素治疗的慢性阻塞性肺病基底细胞。该微阵列的结果表明参与慢性阻塞性肺病细胞组织发育和上皮分化的基因失调。有趣的是，这两条途径中最重要的差异调节基因是参与肺形态发生的基因 HOXA1 和 HOXB2。在正常基底细胞中，HOXA1在基底细胞中高表达，而HOXB2在基底细胞中表达培养两周时增加，并与细胞极化相关，这是分化的先决步骤。 COPD 基底细胞 HOXA1 和 HOXB2 的表达以及槲皮素治疗均显着降低两个基因的表达增加。基于这些观察，我们将检验一个新的假设：槲皮素通过调节 HOXA1 和 HOXB2 纠正失调的修复机制，从而改善对呼吸道感染的免疫反应和慢性阻塞性肺病的肺功能。在具体目标 1 中，我们将确定 HOXA1和HOXB2在气道上皮再生中的作用，以及槲皮素是否可以纠正气道上皮再生通过调节这些 HOX 基因来修复 COPD 失调的机制。在具体目标 2 中，我们将研究槲皮素诱导HOXA1和HOXB2参与再生的分子机制气道上皮。在具体目标 3 中，我们将检查槲皮素诱导的 HOXA1 和 HOXB2 是否参与限制对鼻病毒感染的过度先天免疫反应并防止肺部疾病的进展慢性阻塞性肺病。最后，我们将确认槲皮素治疗是否可以减少慢性阻塞性肺病的气道上皮重塑患者并与 HOXA1 和 HOXB2 的表达相关。完成这些研究将提供对气道上皮再生和槲皮素减少气道的机制的重要见解 COPD 中的上皮重塑。