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

描述（由申请人提供）：慢性肺部疾病，如COPD，其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常伴有粘液淤滞，易受感染和炎症。气道粘蛋白，尤其是MUC5AC和MUC5B，是黏液凝胶的主要成分，在黏毛清除中起重要作用。根据我们实验室最近所做的蛋白质组学研究，超过100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有关。很少有研究调查黏液蛋白/黏液成分在COPD中的作用，而且那些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COPD粘液病理是由“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/或性质。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，黏液的分子组成、黏液蛋白的浓度和大分子组织都发生了改变——无论是在基线还是在加重期间。这些改变产生一种具有异常流变学的粘液，通过正常的纤毛和咳嗽清除机制难以运输。为了验证这些假设，我们使用了广泛的生化、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的比例，[ii]蛋白水解对粘蛋白整体聚合结构的影响，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，来自正常对照、健康吸烟者和COPD患者。在基线和恶化时。在最广泛的层面上，本提案的主要科学目标是比较大量正常对照和COPD患者以及患者群体中的测量参数，从而实现COPD患者的亚分类和生物标志物的发现，这与SPIROMICS的主要目标一致。建议的研究需要获得更综合的观点，从而设计更合理的治疗方法来治疗高分泌状态，如慢性阻塞性肺病。公共卫生相关性：慢性阻塞性肺疾病（COPD）的特点是粘液分泌过多，这通常会加剧发病率并加速死亡率。在最广泛的层面上，该提案的主要科学目标是，使用通过“COPD研究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，在基线和加重时，比较大量正常对照和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。使COPD患者的亚分类和发现生物标志物成为可能，这在将来作为临床试验的中间结果指标是有用的。

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.