Airway mucus/mucin composition and proteome in COPD: A SPIROMICS ancillary study

COPD 中的气道粘液/粘蛋白组成和蛋白质组：SPIROMICS 辅助研究

基本信息

批准号：
8323313
负责人：
Mehmet Kesimer
金额：
$ 37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-22 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323313
关键词：
Alveolar Ancillary Study Biochemical Biological Assay Biological Markers Bronchoscopy Chronic Obstructive Airway Disease Chronic lung disease Classification Clinical Trials Coughing Coupled Detection Electron Microscopy Environment Enzyme-Linked Immunosorbent Assay Excision Future Gel Gel Chromatography Gland Goals Hypertrophy Infection Inflammation Knowledge Laboratories Lasers MUC5AC gene MUC5B gene Mass Spectrum Analysis Measures Methods Modality Molecular Morbidity - disease rate Mucins Mucociliary Clearance Mucous body substance Nature Observational Study Obstruction Outcome Measure Particulate Pathogenesis Pathology Patients Peptide Hydrolases Play Predisposition Property Protease Inhibitor Proteins Proteolysis Proteome Proteomics Publishing Pulmonary Emphysema Refractometry Relative (related person)Rheology Role Sampling Sepharose Smoker Smoking Solvents Source Sputum Structure Testing Therapeutic Therapeutic Intervention Toxin Ultracentrifugation Western Blotting base design disease characteristic globular protein light scattering macromolecule mortality non-smoker non-smoking pathogen patient population prevent protein complex

项目摘要

DESCRIPTION (provided by applicant): Chronic lung diseases such as COPD are characterized by a hypersecretion of mucus, which often exacerbates morbidity and hastens mortality. A characteristic of these diseases is that they are often accompanied by mucus stasis and enhanced susceptibility to infection and inflammation. Airway mucins, particularly MUC5AC and MUC5B, are the major constituent of the mucus gel and play an important role in the mucociliary clearance. Over a hundred other proteins contribute mucus structure, of which approximately half are associated with mucins in some fashion, according to recent proteomic studies done in our laboratory. There are very few studies investigating the mucin/mucus composition in COPD, and those that have been published are based on very small populations of patients. Additionally, we do not know whether COPD mucus pathology results from a simple accumulation of "normal" mucus, or whether the mucus has an abnormal mucin composition and/or properties. Our overall hypothesis, based upon our previous and ongoing studies, is that the molecular composition of the mucus and the concentration and macromolecular organization of its mucins are altered in the COPD environment -- both in baseline and during exacerbations. These alterations produce a mucus that has an aberrant rheology, that is poorly transportable by normal ciliary and cough clearance mechanisms. In testing these hypotheses, using a broad range of biochemical, biophysical and proteomics methods, we propose to assess, [i] mucin concentration and the ratio of MUC5AC/MUC5B, [ii] the effects of proteolysis on overall mucin polymeric structure, and [iii] the dynamic interplay between mucins and interacting proteins, using samples of mucus obtained through "Subpopulations and intermediate outcome measures in COPD study" (SPIROMICS), from normal controls, healthy smokers, and COPD patients, both at baseline and exacerbation. At the broadest level, the major scientific goal of this proposal is to compare the measured parameters over a large number of normal controls and COPD patients, and within the patient population, to enable the sub-classifications of COPD patients and discovery of biomarkers, consistent with the main goals of SPIROMICS. The proposed studies are needed to achieve a more integrated view and thus more rational approaches for designing effective therapeutic modalities to the treatment of hypersecretory states such as COPD.

描述（由申请人提供）：慢性肺病（例如慢性阻塞性肺病）的特征是粘液分泌过多，这通常会加剧发病率并加速死亡率。这些疾病的一个特点是它们常常伴有粘液瘀滞以及对感染和炎症的易感性增强。气道粘蛋白，特别是MUC5AC和MUC5B，是粘液凝胶的主要成分，在粘液纤毛清除中发挥重要作用。根据我们实验室最近进行的蛋白质组学研究，一百多种其他蛋白质有助于粘液结构，其中大约一半以某种方式与粘蛋白相关。很少有研究调查慢性阻塞性肺病中的粘蛋白/粘液成分，并且已发表的研究都是基于非常小的患者群体。此外，我们不知道慢性阻塞性肺病粘液病理学是否是由“正常”粘液的简单积累引起的，或者粘液是否具有异常的粘蛋白成分和/或特性。基于我们之前和正在进行的研究，我们的总体假设是，粘液的分子组成及其粘蛋白的浓度和大分子组织在慢性阻塞性肺病环境中发生了改变——无论是在基线还是在恶化期间。这些改变产生的粘液具有异常的流变性，正常的纤毛和咳嗽清除机制很难输送这种粘液。在测试这些假设时，我们使用广泛的生物化学、生物物理和蛋白质组学方法，建议评估，[i] 粘蛋白浓度和 MUC5AC/MUC5B 的比率，[ii] 蛋白水解对整体粘蛋白聚合结构的影响，以及 [ iii] 粘蛋白和相互作用蛋白之间的动态相互作用，使用通过“慢性阻塞性肺病研究中的亚群和中间结果测量”（SPIROMICS）获得的粘液样本，来自正常对照、健康吸烟者，和慢性阻塞性肺病患者，无论是在基线还是恶化时。在最广泛的层面上，该提案的主要科学目标是比较大量正常对照和 COPD 患者以及患者群体内的测量参数，以实现 COPD 患者的细分和生物标志物的发现， SPIROMICS 的主要目标。需要进行拟议的研究来获得更综合的观点，从而设计更合理的方法来设计治疗慢性阻塞性肺病等分泌过多状态的有效治疗方式。