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

• 批准号: 8215467
• 负责人: Mehmet Kesimer
• 金额: $ 33.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8215467
• 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

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. PUBLIC HEALTH RELEVANCE: Chronic obstructive lung disease (COPD) is characterized by a hypersecretion of mucus, which often exacerbates morbidity and hastens mortality. At the broadest level, the major scientific goal of this proposal, using samples of mucus obtained through "Subpopulations and intermediate outcome measures in COPD study" (SPIROMICS) from smokers, and COPD patients, both at baseline and exacerbation, is to compare the mucin properties and mucin-interacting proteins 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 which is useful in the future as intermediate outcome measures for clinical trials.

描述(申请人提供)：慢性肺部疾病，如慢性阻塞性肺病，以粘液过度分泌为特征，这通常会加剧发病率和加速死亡。这些疾病的一个特点是经常伴有粘液淤积，对感染和炎症的易感性增加。呼吸道粘蛋白，尤其是MUC5AC和MUC5B，是粘液凝胶的主要成分，在粘液纤毛清除中起着重要作用。根据我们实验室最近进行的蛋白质组学研究，超过100种其他蛋白质影响粘液结构，其中大约一半与粘蛋白以某种方式相关。研究慢性阻塞性肺疾病的粘蛋白/粘液成分的研究很少，已经发表的那些研究是基于非常小的患者群体。此外，我们不知道COPD的粘液病理是由于“正常”粘液的简单堆积，还是粘液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，在COPD环境中，粘液的分子组成及其粘蛋白的浓度和大分子组织都会发生变化--无论是在基线还是在病情恶化期间。这些变化产生的粘液具有异常的流变性，通过正常的纤毛和咳嗽清除机制很难运输。在验证这些假说时，我们建议使用广泛的生化、生物物理和蛋白质组学方法，[i]评估粘蛋白浓度和MUC5AC/MUC5B的比率，[ii]蛋白分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“COPD研究中的亚群和中间结果测量”(SPIROMICS)获得的粘液样本，这些样本来自正常对照组、健康吸烟者和COPD患者，在基线和恶化时都是如此。在最广泛的层面上，这项建议的主要科学目标是比较大量正常对照和COPD患者以及患者群体中的测量参数，以便能够根据SPIROMICS的主要目标对COPD患者进行细分和发现生物标记物。建议的研究需要实现更综合的观点，从而为设计有效的治疗方式来治疗COPD等高分泌状态提供更合理的方法。公共卫生相关性：慢性阻塞性肺疾病(COPD)的特征是粘液过度分泌，这往往会加剧发病率和加速死亡。在最广泛的层面上，这项建议的主要科学目标是使用通过“COPD研究中的亚群和中间结果测量”(SPIROMICS)从吸烟者和COPD患者中获得的粘液样本，在基线和病情恶化时，比较大量正常对照组和COPD患者以及患者群体中的粘蛋白特性和粘蛋白相互作用蛋白，从而能够对COPD患者进行亚类分类，并发现可用于未来临床试验的中间结果测量的生物标记物。