Mucus Microstructure and Osmotic Pressure: Biomarkers for CB in COPD

粘液微观结构和渗透压：COPD 中 CB 的生物标志物

基本信息

批准号：
8852864
负责人：
Justin S. Hanes
金额：
$ 44.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852864
关键词：
Acute Affect Biochemical Biological Markers Cells Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Clinical Coughing DNA Data Development Disease Disease Progression Epithelial Cells Exercise Focal Infection Frequencies Future Gastroesophageal reflux disease Gel Grant Hygiene Inflammatory Injury Ions Lead Link Measurement Measures Methodology Mortality Decline Mucins Mucous body substance Observational Study Osmotic Pressure Outcome Parents Pathology Patients Persons Phase Population Population Study Prevalence Production Property Quality of life Recruitment Activity Reporting Resolution Respiratory physiology Sampling Severities Severity of illness Smoker Solid Specific qualifier value Specimen Sputum Staging Stereotyping Symptoms Testing Therapeutic Trials Visit abstracting adverse outcome airway epithelium airway obstruction base biophysical properties cigarette smoking clinical research site cohort design disease classification follow-up innovation mucus hypersecretion nanoparticle novel particle patient population public health relevance targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Mucus clearance, a critical mechanism for airway hygiene, relies on the biophysical properties of the mucus gel. In COPD, quantitative and qualitative changes in mucus contribute to airway obstruction, exacerbation rate, accelerated lung function decline and mortality. This COPD subphenotype, also known as chronic bronchitis (CB), affects up to 70% of patients with the disorder. Despite the prevalence, complexity and importance of mucus hypersecretion in COPD, our understanding of the qualitative changes in mucus that accompany COPD development and progression is quite limited. Given that the CB subphenotype of COPD, referred to as COPD-CB, is intimately linked to adverse outcomes, a better understanding of the signature pathology in this disorder may lead to more effective targeted therapies and more practical disease classifications. We have pioneered the use of high resolution multiple particle tracking of muco-inert nanoparticles, termed particle tracking-based structural analysis (PTSA), to probe mucus microstructure. Using this approach in addition to mucus content measurements, we have found that distinct properties of spontaneously expectorated sputum obtained from COPD patients associate with disease severity. We also have found that elevated solid content increases osmotic pressure in COPD sputum samples, which in turn impairs mucus clearance by collapsing periciliary layer above the airway epithelium. One of the stated objectives of SPIROMICS is a more refined characterization of COPD subphenotypes. We submit that a detailed assessment of the properties of spontaneous sputum samples obtained from a large, well-defined, study population of COPD-CB patients in the SPIROMICS cohort will avail informative biophysical and biochemical measures, which associate with disease severity and progression. Our hypotheses are 1) altered mucus microstructure, specifically, a tightening of the mucus mesh, and increased osmotic pressure associates with worsened lung function, accelerated lung function decline, increased symptoms, and worse quality of life in the COPD-CB population 2) frequent exacerbators will display stereotyped mucus alterations in both acute and quiescent settings. We plan to collect spontaneous expectorated sputum samples from 150 SPIROMICS patients who report cough and chronic sputum production at four clinical sites/subsites and assess osmotic pressure and microstructure using the innovative PTSA methodology, in addition to conventional biochemical analyses of sputum constituents.

描述（由申请人提供）：粘液清除是气道卫生的关键机制，依赖于 COPD 中粘液凝胶的生物物理特性，粘液的数量变化会导致气道阻塞、恶化率、加速肺功能下降和死亡率。 COPD 亚表型，也称为慢性支气管炎 (CB)，影响着高达 70% 的该疾病患者，尽管 COPD 中粘液分泌过多的患病率、复杂性和重要性，但我们的理解是。鉴于 COPD 的 CB 亚型（称为 COPD-CB）与不良后果密切相关，因此更好地了解这种疾病的特征病理学可能会导致 COPD 发生和进展所伴随的粘液质变化。我们率先使用粘液惰性纳米粒子的高分辨率多粒子追踪（称为基于粒子追踪的结构分析（PTSA））来探测粘液微观结构。根据粘液含量测量，我们发现从 COPD 患者获得的自发预期痰液的独特特性与疾病严重程度相关。我们还发现，固体含量会增加 COPD 痰液样本中的渗透压，这反过来又会因纤毛周围层塌陷而损害粘液清除率的提高。 SPIROMICS 的既定目标之一是对 COPD 亚表型进行更精细的表征。从 SPIROMICS 队列中大量、明确的 COPD-CB 患者研究群体中获得的痰样本将利用与疾病严重程度和进展相关的信息丰富的生物物理和生化测量，我们的假设是 1) 改变的粘液微观结构，特别是粘液微观结构。粘液网收紧和渗透压增加与 COPD-CB 人群的肺功能延长、肺功能加速衰退、症状增加和生活质量较差相关 2) 频繁的加重者将表现出刻板印象我们计划从 150 名 SPIROMICS 患者那里收集自发的预期痰样本，这些患者在四个临床中心/亚中心报告有咳嗽和慢性痰液产生，并使用创新的 PTSA 方法以及传统方法评估渗透压和微观结构。痰成分的生化分析。