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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：
10296535
负责人：
Umadevi Sivanappa Sajjan
金额：
$ 55.37万
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/10296535
关键词：
Affect Airway Disease Anti-Inflammatory Agents Antioxidants Basal Cell Basal Cell Hyperplasia CDH1 gene Cell Culture Techniques Cell Cycle Cell Differentiation process Cell Proliferation Cells Chronic Obstructive Airway Disease Consumption Data Development Diet Epithelial Epithelial Cells Genes Goblet Cells HOX protein Health Health Benefit Homeobox Genes Homeostasis Human Immune response Infection Injury Innate Immune Response Knockout Mice Lead Lung Lung Inflammation Lung diseases Maintenance Metaplastic Cell Metaplastic Squamous Cell Molecular Morphogenesis Mus Natural Immunity Natural regeneration Outcome Pathologic Pathway interactions Patients Placebos Play Property Publishing Quercetin Regenerative pathway Regulation Repression Research Respiratory Tract Infections Rhinovirus Rhinovirus infection Role STC2 gene Signal Transduction Site Structure Testing Tissues adaptive immune response adaptive immunity airway epithelium airway regeneration airway remodeling base bronchial epithelium chemokine cytokine disease phenotype epithelial repair epithelium regeneration improved insight knock-down mouse model non-smoker novel polarized cell polyphenol prevent 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.

项目总结