Longitudinal Analysis of Transcriptomic Endophenotypes in Asthma

描述（由申请人提供）： 尽管哮喘的潜在致病机制存在差异，但驱动肺生物学的基本过程存在于大多数（如果不是全部）损伤和修复反应中。然而，一个主要的挑战是确定这些条件中存在的共同模式。目前，哮喘表型的定义是有限的，依赖于过敏史、发病年龄、肺功能和症状严重程度等特征的临床范例不精确。“这些研究，包括严重哮喘研究计划（SARP）对哮喘簇的表征，是有用的，但受到人口统计学和生理变量差异的影响，这些变量与疾病的许多生物学方面无关。整合功能基因组学有可能在反映真正的内在表型的水平上定义哮喘内在表型，这些内在表型在机制上是重要的哮喘的发病机制为此，我们的多学科研究团队开发了一种分子表型分析方案，使用在哮喘患者的痰液和循环中测量的全基因组基因表达来评估转录组哮喘内表型，并确定了3种哮喘转录内表型（痰液TEA簇）。TEA组1具有低水平的气道炎症和最可逆的气道阻塞; TEA组2具有中等量的气道炎症、可逆的气流阻塞和高的痰IL-13水平（Th 2簇）; TEA组3的气道炎症水平最高，可逆性气道阻塞最少（重塑簇）和高水平的痰YKL-40（我们已经证明与重塑和严重哮喘相关的几丁质酶样蛋白）。此外，使用来自该队列的匹配血液基因表达数据，我们开发了一种使用69个基因的预测模型，该模型可以以85%的准确度确定个体的痰TEA簇分配。总之，这些数据表明，转录衍生的哮喘内表型与气道炎症，生理重塑，和免疫表型相关的细胞因子。在本申请中，整合功能基因组学将用于评估TEA簇模型的稳定性。将纵向研究第二个独立的哮喘受试者队列，并确定与TEA簇相关的先天性和适应性免疫系统应答。将评估TEA簇对其他肺部疾病的可推广性，以鉴定与TEA簇相关的基本表达网络。最终，这些研究将提高我们在疾病部位分子水平上对哮喘异质性的理解，并确定具有相似基因网络调节的患者。研究结果将产生新的哮喘内表型分子诊断，可用于使用血液和痰液基因表达对患者进行病因和治疗研究的亚分类，并确定候选基因研究的新靶点。

DESCRIPTION (provided by applicant): PROJECT SUMMARY Despite differences in the underlying pathogenic mechanisms of asthma, the fundamental processes that drive lung biology are present across most, if not all, injury and repair responses. However, a major challenge is the identification of common patterns present in these conditions. Currently, asthma phenotypes have been defined in limited terms and imprecise clinical paradigms that rely on features such as allergic history, age of onset, lung function, and symptoms of "severity." These studies, including the Severe Asthma Research Program (SARP) characterization of asthma clusters, have been useful, but are driven by differences in demographic and physiologic variables, measures that are distal to many biologic aspects of the disease.4 In contrast to these approaches, integrative functional genomics has the potential to define asthma endophenotypes at a level reflective of true endophenotypes that are mechanistically important to the pathogenesis of asthma. To this end, our multidisciplinary research team has developed a molecular phenotyping protocol to evaluate transcriptomic asthma endophenotypes using genome-wide gene expression measured in the sputum and circulation of asthmatics and has identified 3 transcriptional endophenotypes of asthma (sputum TEA clusters). TEA cluster 1 has a low level of airway inflammation and the most reversible airway obstruction; TEA cluster 2 has a moderate amount of airway inflammation, reversible airflow obstruction, and high sputum IL-13 levels (Th2 cluster); and TEA cluster 3 has the highest level of airway inflammation, the least reversible airway obstruction (remodeled cluster), and high levels of sputum YKL-40 (a chitinase-like-protein we have shown to be associated with remodeling and severe asthma). In addition, using matched blood gene expression data from this cohort, we developed a predictive model using 69 genes that can determine an individual's sputum TEA cluster assignment with 85% accuracy. Taken together, these data demonstrate that transcriptomically-derived asthma endophenotypes are associated with airway inflammation, physiologic remodeling, and immunophenotype-associated cytokines. In this application, integrative functional genomics will be used to evaluate the stability of the TEA cluster model. A second independent cohort of asthma subjects will be studied longitudinally, and the innate and adaptive immune system responses associated with the TEA clusters will be determined. The generalizability of TEA clusters to other lung diseases will be evaluated to identify the fundamental expression networks associated with the TEA clusters. Ultimately, these studies will improve our understanding of asthma heterogeneity at the molecular level at the site of disease, and identify patients with similar modulation of gene networks. The results will generate new molecular diagnoses of asthma endophenotypes that can be used to sub-classify patients for pathogenetic and therapeutic studies using blood and sputum gene expression and identify novel targets for candidate gene studies.