Novel asthma pathogenesis genes in the mucosa of the human airways

 描述(申请人提供)：尽管全球正在努力了解特定呼吸道疾病的发病机制，包括越来越多的转录组学和全基因组关联研究，但与哮喘发展有关的机制仍然难以捉摸。哮喘常与上呼吸道并存疾病、过敏性鼻炎和慢性鼻窦炎有关。这些观察结果导致了“统一呼吸道”假说，即上呼吸道和下呼吸道可能在免疫上是联系在一起的，这一事实得到了所有呼吸道形成与环境相互作用的连续粘膜上皮屏障的支持。此外，上皮屏障的破坏最近被认为是变态反应性疾病发展的核心。将哮喘作为“统一呼吸道”的一种屏障疾病是一种策略，可以提供对其发病机制的更深层次的理解。使用一种新的比较多研究生物信息学方法，我们已经确定了新的基因(包括ELF5、FGFR2、KLF4、SNAI2、TGM2和WNT4)和几个未被识别的、令人兴奋的生物学主题，支持统一的气道概念。我们对这些过程的初步测试表明，它们汇聚在一个促进上皮去分化的潜在机制上，该机制可能是由发育和核激素信号的异常整合驱动的，以促进上皮的动态平衡。我们已经组建了一个强大的跨学科团队来测试统一的气道假说，该假说认为共同的全身过程是两个气道位置过敏疾病的病理基础，具体目标如下： 1)发现哮喘的新途径并确定统一呼吸道疾病的遗传特征，这将有助于哮喘发病机制的研究；2)确认假定的生物标志物的粘膜起源，验证其在哮喘患者中的表达，并测试这些基因在独立的哮喘患者队列中的诊断作用。我们对我们的初步发现深感鼓舞，并预计我们的新方法将提供显著影响我们对哮喘和呼吸道过敏性疾病发病机制的理解的信息。

 DESCRIPTION (provided by applicant): Despite increasing global efforts to understand the pathogenesis of specific airway diseases, including a growing number of transcriptomics and genome-wide association studies, mechanisms linked to development of asthma remain elusive. Asthma is frequently associated with co-morbid diseases of the upper airways, allergic rhinitis and chronic rhinosinusitis. These observations have led to the "unified airway" hypothesis that the upper and lower airway may be immunologically linked, supported by the fact that all airways form a continuous mucosal epithelial barrier interacting with the environment. Moreover, epithelial barrier disruption has been recently implicated as central to the development of allergic disease. Approaching asthma as a barrier disease of the "unified airway" is one strategy that could provide a deeper understanding of its pathogenesis. Using a novel comparative multi-study bioinformatics approach, we have identified novel genes (including ELF5, FGFR2, KLF4, SNAI2, TGM2 and WNT4) and several unrecognized and exciting biological themes supporting the unified airway concept. Our preliminary testing of these processes suggests that they converge on an underlying mechanism promoting epithelial de-differentiation that is likely driven by aberrant integration of developmental and nuclear hormonal signaling for epithelial homeostasis. We have assembled a strong cross-disciplinary team to test the unified airway hypothesis, which holds that common systemic processes underlie pathology of allergic disease at both airway locations, with the following specific goals: 1) to discover novel pathways for asthma and identify genetic signatures of unified airway disease, which would facilitate the study of asthma pathogenesis at either airway location; 2) to confirm mucosal origins of putative biomarkers, validate their expression and test diagnostic utility of these genes in an independent cohort of asthma patients. We are strongly encouraged by our preliminary findings, and anticipate that our novel approaches will provide information that will significantly impact our understanding of the pathogenesis of asthma and allergic diseases of the airway.