Phenotypic and biological features of mucus plugs in asthma

项目总结/摘要 我们发表的数据显示，半定量粘液栓评分与气道测量密切相关， 2型炎症与哮喘气流阻塞我们现在已经开发出了新的方法， 半定量粘液栓评分到详细的定量粘液栓表型（粘液栓数目， 大小和位置），这项技术使我们能够更深入地探索哮喘中的粘液栓生物学。我们 更新补助金申请将继续利用CT肺部图像和气道生物标本资源， SARP-3队列，利用Fahy博士建立的成像团队探索气道粘液栓表型 使用CT肺部图像，并继续Fahy博士和Seibold博士实验室之间的持续合作， 解决哮喘的发病机制。目的1将探讨2型气道粘液栓 炎症和气流阻塞。我们对粘液栓和2型炎症的研究将包括分析 在SARP-3患者开始治疗蛋白靶向治疗之前和之后， 第二种途径。我们对粘液栓和气道位置的研究旨在确定 粘液堵塞和气道大小是气流限制的最重要因素。目标2将确定是否 吸入N-乙酰半胱氨酸（NAC）治疗改善高粘液哮喘的气流。NAC具有粘液溶解性 因为它能切断粘蛋白聚合物之间过多的二硫键， 哮喘的弹性我们的临床试验将直接测试粘液栓导致气流限制的假设， 哮喘，并确定粘液栓表型对粘液溶解治疗反应的影响。目标3将 确定ITLN 1在哮喘气道粘液栓病理生理学中的作用。Intelectin-1（ITLN 1）是一种 我们的初步数据显示，一个eQTL是由IL-13（一种2型细胞因子）上调的上皮细胞蛋白， ITLN-1变异改变哮喘中粘液堵塞的风险。这为我们探索机制提供了动力 ITLN-1介导的粘液病理学。我们的目标有具体的假设， 通过强大的初步数据，并通过应用最先进的成像，计算机视觉， 细胞和分子方法学。我们的研究有望促进对粘液栓的了解 严重哮喘患者的生物学，我们的数据将为粘液栓药物的开发提供信息， 治疗性支气管镜检查的潜在效用。最重要的是，我们的CT粘液表型生物标志物将 为该领域提供了急需的高粘液哮喘的预测和监测生物标志物。

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.