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: 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
• 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

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）：诸如COPD之类的慢性肺部疾病的特征是粘液过度分泌，这通常会加剧发病率并加快死亡率。这些疾病的一个特征是它们通常伴随着粘液浸泡，并增强了对感染和炎症的敏感性。气道粘蛋白，尤其是MUC5AC和MUC5B是粘液凝胶的主要组成部分，在粘膜纤毛间隙中起重要作用。根据我们实验室中最近进行的蛋白质组学研究，超过一百种蛋白质促成粘液结构，其中大约一半与粘蛋白相关。很少有研究COPD中粘蛋白/粘液组成的研究，而已发表的研究是基于很少的患者人群。此外，我们不知道COPD粘液病理学是由“正常”粘液的简单积累引起的，还是粘液具有异常的粘蛋白组成和/或特性。我们的总体假设是基于我们以前的研究和正在进行的研究，是粘液的分子组成以及其粘蛋白的浓度和大分子组织在COPD环境中发生了变化 - 无论是在基线还是在加剧过程中。这些改变会产生一种具有异常流变学的粘液，通过正常睫状和咳嗽清除机制的运输差。在测试这些假设时，使用多种生化，生物物理和蛋白质组学方法，我们建议评估[I]粘蛋白浓度和MUC5AC/MUC5B的比率，[ii]蛋白水解对整体粘液蛋白聚合结构和[III]使用动态互动的蛋白质的影响COPD研究中的中级结局指标”（螺旋学），正常对照，健康吸烟者和COPD患者，无论是在基线和加重时。在最广泛的水平上，该提案的主要科学目标是比较大量正常对照和COPD患者以及患者人群中的测量参数，以使COPD患者的亚分类和发现生物标志物的亚分类，并与螺旋组学的主要目标一致。需要进行拟议的研究来实现更综合的观点，从而为设计有效的治疗方法来治疗COPD等高分泌状态，以设计有效的治疗方式。