Pulmonary bacterial microbiome-epithelial cell interactions in COPD

COPD 中肺部细菌微生物组与上皮细胞的相互作用

• 批准号: 8337156
• 负责人: Gary B Huffnagle
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337156
• 关键词: Ancillary Study; Bacteria; Cell Communication; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Communities; Complex; Coughing; Data; Diagnostic; Disease; Disease Progression; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Gene Expression; Gene Expression Profile; Genes; Health Status; Immune response; Indigenous; Industry; Infection; Inflammation; Inflammatory Response; Investigation; Lead; Libraries; Ligands; Lung; MUC5AC gene; Mediating; Methodology; Methods; Microbe; Microbiology; Molecular; Morbidity - disease rate; Mucins; Mucous Membrane; Mucous body substance; Organism; Outcome; Parents; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Peptides; Placebos; Play; Process; Production; Pseudomonas; Receptor Activation; Receptor Signaling; Recurrence; Regulation; Reporting; Respiratory System; Respiratory physiology; Respiratory tract structure; Role; Sampling; Science; Site; Sputum; Structure; Symptoms; System; Systems Biology; Techniques; Therapeutic; airway inflammation; airway obstruction; antimicrobial; arm; base; biological adaptation to stress; c-erbB-1 Proto-Oncogenes; clinical phenotype; high throughput technology; improved; in vivo; indexing; inhibitor/antagonist; insight; mathematical model; microbial; microbial community; microbiome; mortality; novel; novel therapeutics; phosphoric diester hydrolase; receptor expression; research study; resilience; response

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. PUBLIC HEALTH RELEVANCE: COPD is a highly prevalent disorder with rising mordibity, mortality and limited therapeutic options. This ancillary study provides an unparalleled opportunity to examine longitudinal changes in airway microbial composition and identify relationships between inflammation and mucus production that may lead to improved diagnostics and/or therapeutics.

描述（由申请人提供）：COPD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。咳嗽和咳痰占优势的患者被认为是具有更大气道炎症的独特表型组;然而，COPD中持续性炎症的潜在因素仍未得到解决。该提案的母研究检查了罗氟司特（一种有效且特异性的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，这些与炎症，上皮基因表达和粘蛋白产生的变化。该建议的中心假设是COPD患者的固有肺微生物组的变化（整体群落结构的变化或通过单一物种或有限细菌聚生体对肺粘膜的支配/定殖）引起上皮细胞基因表达的变化，包括EGFR途径的激活和粘蛋白诱导，从而导致COPD患者的气道阻塞和慢性支气管炎的症状。这一过程将通过PDE4抑制剂来改善。具体而言，我们将1）确定COPD患者气道样本中的微生物群落; 2）确定COPD中气道上皮粘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粘蛋白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（PRR）的上皮基因表达之间的关系，抗微生物肽和宿主应激反应途径; 4）研究细菌微生物组的变化（纵向和通过罗氟司特）与上皮粘蛋白调节、上皮基因表达、气道炎症和临床表型之间的相互关系，使用数学模型来识别潜在的相互作用。该提案将利用行业赞助的大型研究，采用最先进的方法，在一组高度特征化的慢性支气管炎COPD受试者中检查复杂的微生物群落、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，为肺部微生物群变化对高度特征化的COPD受试者疾病变化的贡献提供新的见解。 公共卫生相关性：COPD是一种高度流行的疾病，发病率、死亡率不断上升，治疗选择有限。这项辅助研究提供了一个无与伦比的机会，以检查气道微生物组成的纵向变化，并确定炎症和粘液产生之间的关系，可能会导致改善诊断和/或治疗。