Novel asthma pathogenesis genes in the mucosa of the human airways

 描述（由申请人提供）：尽管全球越来越多地努力了解特定气道疾病的发病机制，包括越来越多的转录组学和全基因组关联研究，但与哮喘发生相关的机制仍然难以捉摸。哮喘常与上呼吸道的共病、过敏性鼻炎和慢性鼻窦炎有关。这些观察结果导致了"统一气道"假说，即上气道和下气道可能是免疫学上联系的，这得到了所有气道形成与环境相互作用的连续粘膜上皮屏障的事实的支持。此外，上皮屏障破坏最近被认为是过敏性疾病发展的核心。将哮喘作为“统一气道”的屏障疾病是一种可以更深入了解其发病机制的策略。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）和几个未被识别和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，它们聚集在一个促进上皮去分化的潜在机制上，这可能是由上皮稳态的发育和核激素信号传导的异常整合驱动的。我们组建了一个强大的跨学科团队来测试统一的气道假设，该假设认为两个气道位置的过敏性疾病的病理学基础是共同的全身过程，具体目标如下： 1)发现哮喘的新途径，并确定统一的气道疾病的遗传特征，这将有助于研究哮喘发病机制在任何气道位置; 2）确认粘膜来源的假定的生物标志物，验证他们的表达和测试这些基因的诊断效用在一个独立的队列哮喘患者。我们的初步研究结果令我们深受鼓舞，并预计我们的新方法将提供信息，将显着影响我们对哮喘和气道过敏性疾病的发病机制的理解。

 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.