Phenotypic and biological features of mucus plugs in asthma

项目摘要/摘要 我们公布的数据显示，半定量粘液堵塞评分与呼吸道指标密切相关。 哮喘中的2型炎症和气流阻塞。我们现在已经开发了新的方法来从 半定量粘液塞子评分以详细定量粘液塞子表型(粘液塞子数， 大小和位置)，这项技术使我们能够更深入地探索哮喘的粘液堵塞生物学。我们的 续期拨款申请将继续利用CT肺部图像和来自 SARP-3队列，利用Fahy博士建立的成像团队探索呼吸道粘液堵塞表型 使用CT肺部图像，并继续法希博士和塞博尔德博士的实验室之间的持续合作，共同 研究哮喘的疾病机制。目标1将探索呼吸道粘液塞与2型之间的关系 炎症和气流阻塞。我们对粘液堵塞和II型炎症的研究将包括分析 SARP-3患者开始治疗性蛋白质靶向治疗前后呼吸道粘液塞子的变化 第二类途径。我们对粘液堵塞和呼吸道位置的研究旨在确定 粘液塞和对气流受限影响最大的气道大小。目标2将决定是否 吸入N-乙酰半胱氨酸(NAC)可改善粘液高哮喘患者的气流。NAC是粘液溶解的 因为它裂解了粘蛋白聚合物之间过多的二硫键，从而增加了呼吸道粘液凝胶 哮喘的弹性。我们的临床试验将直接测试粘液堵塞导致气流受限的假设 并确定粘液堵塞表型对粘液溶解治疗反应的影响。目标3将 确定ITLN1在哮喘呼吸道粘液堵塞的病理生理学中的作用。Inteltin-1(ITLN1)是一种 由IL-13(一种2型细胞因子)上调的上皮细胞蛋白，我们的初步数据表明，一个eQTL ITLN-1的变异改变了哮喘粘液堵塞的风险。这为我们探索机制提供了动力 在台架实验中研究ITLN-1介导的粘液病理。我们的目标有具体的假设，得到了支持 通过稳健的初步数据，并通过应用最先进的成像、计算机视觉和 细胞和分子方法学。我们的研究有望促进对粘液堵塞的了解 严重哮喘患者的生物学和我们的数据将为粘液塞和 治疗性支气管镜检查的潜在用途。最重要的是，我们的CT粘液表型生物标记物 为粘液性哮喘提供急需的预测和监测生物标记物。

Project Summary / Abstract Our published data reveals that semi quantitative mucus plug scores strongly associate with measures of airway type 2 inflammation and airflow obstruction in asthma. We have now developed novel approaches to move from a semi-quantitative mucus plug score to detailed quantitative mucus plug phenotyping (mucus plug number, size, and location), and this technology allows us to more deeply explore mucus plug biology in asthma. Our renewal grant application will continue to leverage CT lung images and airway biospecimen resources from the SARP-3 cohort, take advantage of an imaging team built by Dr Fahy to explore airway mucus plug phenotypes using CT lung images, and continue an ongoing collaboration between Dr Fahy’s and Dr Seibold’s labs to jointly tackle disease mechanisms in asthma. Aim 1 will explore relationships between airway mucus plugs, type 2 inflammation and airflow obstruction. Our studies of mucus plugs and type 2 inflammation will include analysis of airway mucus plugs in SARP-3 patients before and after they were started on therapeutic proteins targeting the type 2 pathway. Our studies of mucus plugs and airway location are designed to determine the number of mucus plugs and the airway sizes that are most consequential for airflow limitation. Aim 2 will determine if treatment with inhaled N-acetylcysteine (NAC) improves airflow in mucus-high asthma. NAC is mucolytic because it cleaves the excessive disulfide bridges between mucin polymers that increase airway mucus gel elasticity in asthma. Our clinical trial will directly test the hypothesis that mucus plugs cause airflow limitation in asthma and determine the influence of mucus plug phenotypes on response to mucolytic treatment. Aim 3 will determine the role of ITLN1 in the pathophysiology of airway mucus plugs in asthma. Intelectin-1 (ITLN1) is an epithelial cell protein that is upregulated by IL-13 (a type 2 cytokine), and our preliminary data show that a eQTL variant in ITLN-1 modifies risk of mucus plugging in asthma. This provided impetus for us to explore mechanisms of ITLN-1 mediated mucus pathology in bench experiments. Our aims have specific hypotheses, are supported by robust preliminary data, and are enabled by the application of state of the art imaging, computer vision, and cellular and molecular methodologies. Our research promises to advance understanding about mucus plug biology in patients with severe asthma and our data will inform drug development for mucus plugs and the potential utility of therapeutic bronchoscopy. Most importantly, our CT mucus phenotyping biomarkers will provide the field with much needed predictive and monitoring biomarker for mucus-high asthma.