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

描述（由申请人提供）：慢性肺病如COPD的特征是粘液分泌过多，这通常会加剧发病率并加速死亡。这些疾病的一个特点是，它们往往伴随着粘液淤滞和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，在粘液纤毛清除中起重要作用。根据我们实验室最近进行的蛋白质组学研究，超过一百种其他蛋白质有助于粘液结构，其中大约一半与粘蛋白以某种方式相关。很少有研究调查COPD中的粘蛋白/粘液成分，并且已发表的研究基于非常小的患者人群。此外，我们不知道COPD粘液病理是否由"正常"粘液的简单积累引起，或者粘液是否具有异常的粘蛋白组成和/或性质。基于我们先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COPD环境中发生了改变-无论是在基线还是在加重期间。这些改变产生具有异常流变性的粘液，其通过正常纤毛和咳嗽清除机制的转运性差。在测试这些假设时，使用广泛的生物化学，生物物理学和蛋白质组学方法，我们建议评估，[i]粘蛋白浓度和MUC5AC/MUC5B的比例，[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"COPD研究中的亚群和中间结果测量"（SPIROMICS）从正常对照、健康吸烟者和COPD患者在基线和加重时获得的粘液样品。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患者以及患者人群中的测量参数，以实现COPD患者的子分类和生物标志物的发现，与SPIROMICS的主要目标一致。建议的研究需要实现一个更完整的观点，从而更合理的方法来设计有效的治疗模式，以治疗高分泌状态，如COPD。

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.