Pulmonary bacterial microbiome-epithelial cell interactions in COPD

描述（由申请人提供）：慢性阻塞性肺病是一种发病率和死亡率不断上升的高度流行疾病，改变病程的治疗选择有限。以咳嗽和痰为主的患者被认为是一个明显的表型组，气道炎症较大；然而，慢性阻塞性肺病持续炎症的潜在因素仍未得到解决。本研究的母研究考察了罗氟米司特（一种有效的特异性PDE4抑制剂）与安慰剂对气道炎症的影响。这项辅助研究提供了一个无与伦比的机会来检查气道微生物结构和功能的纵向变化，这些变化与炎症、上皮基因表达变化和粘蛋白产生有关。该建议的中心假设是，COPD患者的本地肺微生物组的变化（无论是整体群落结构的变化，还是通过单一物种或有限细菌群落对肺粘膜的支配/定植）导致上皮细胞基因表达的变化，包括EGFR通路的激活和粘蛋白诱导，从而导致COPD患者气道阻塞和慢性支气管炎症状。PDE4抑制剂将改善这一过程。具体来说，我们将1)定义COPD患者气道样本中的微生物群落；2)确定COPD患者气道上皮黏液蛋白失调的细菌决定因素，以及罗氟司特是否通过减少气道黏液蛋白的产生发挥其有益作用；3)确定细菌微生物组的局部变化与模式识别受体（PRRs）、抗微生物肽和宿主应激反应途径的上皮基因表达之间的关系；4)研究细菌微生物组的变化（纵向和经罗氟司特）与上皮黏液蛋白调节、上皮基因表达、气道炎症和临床表型之间的相互关系，利用数学模型确定潜在的相互作用。该提案将利用行业赞助的大型研究，采用最先进的方法来检查高度特征的COPD伴慢性支气管炎患者的复杂微生物群落、上皮粘蛋白产生和气道炎症。这些新实验产生的数据将利用高通量技术和系统科学方法，为高度特征性COPD受试者的肺微生物群变化对疾病变化的贡献提供新的见解。

DESCRIPTION (provided by applicant): COPD is a highly prevalent disorder with rising mordibity and mortality and there are limited therapeutic options to alter disease course. Patients with a predominance of cough and sputum production are felt to be a distinct phenotypic group with greater airway inflammation; however, the factors underlying persistent inflammation in COPD remain unresolved. The parent study of this proposal examines the effect of roflumilast (a potent and specific PDE4 inhibitor) versus placebo on airway inflammation. This ancillary study provides an unparalled opportunity to examine longitudinal changes in airway microbial structure and function, relating these to inflammation, changes in epithelial gene expression and mucin production. The central hypothesis of this proposal is that changes in the indigenous pulmonary microbiome of COPD patients (either a change in overall community structure or through domination/colonization of the pulmonary mucosa by a single species or limited bacterial consortia) causes changes in epithelial cell gene expression, including activation of the EGFR pathway and mucin induction, thereby contributing to airway obstruction and symptoms of chronic bronchitis in COPD patients. This process will be ameliorated by a PDE4 inhibitor. Specifically, we will 1) define the microbial communities from airway samples in COPD patients; 2) identify bacterial determinants of airway epithelial mucin dysregulation in COPD and whether roflumilast exerts its beneficial effects through reduction in airway mucin production; 3) determine the relationship between localized changes in the bacterial microbiome and epithelial gene expression of pattern recognition receptors (PRRs), anti-microbial peptides and host stress-response pathways and; 4) investigate the interrelationship between changes in the bacterial microbiome (longitudinal & via roflumilast) with epithelial mucin regulation, epithelial gene expression, airway inflammation and clinical phenotype, using mathematical models to identify potential interactions. This proposal will leverage a large, industry sponsored investigation with state of the art methodologies to examine complex microbial communities, epithelial mucin production and airway inflammation in a highly characterized group of COPD subjects with chronic bronchitis. The data generated by these novel experiments will provide novel insight into the contribution of changes in the lung microbiota to changes in disease in highly characterized COPD subjects, utilizing high throughput technologies and systems science approaches.