Longitudinal Analysis of Transcriptomic Endophenotypes in Asthma

哮喘转录组内表型的纵向分析

• 批准号: 8714044
• 负责人: GEOFFREY L CHUPP
• 金额: $ 79.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714044
• 关键词: Age of Onset; Allergic; Asthma; Biology; Blood; Blood Circulation; Candidate Disease Gene; Cells; Characteristics; Chitinase; Chronic; Clinical; Data; Disease; Disorder by Site; Distal; Enrollment; Evaluation; Gene Cluster; Gene Expression; Genes; Heterogeneity; Immune response; Immune system; Immunologics; Immunophenotyping; Individual; Inflammatory; Interdisciplinary Study; Interleukin-13; Longitudinal Studies; Lung; Lung diseases; Measures; Methods; Modeling; Molecular; Molecular Diagnosis; Obstruction; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Population; Process; Proteins; Protocols documentation; Recording of previous events; Recruitment Activity; Reproducibility; Research; Respiratory physiology; Severities; Sputum; Study Subject; Subgroup; Symptoms; Syndrome; System; Therapeutic Studies; Therapeutic Use Study; Time; Weight; Wheezing; airway inflammation; airway obstruction; arm; base; cell type; cohort; cytokine; endophenotype; functional genomics; genome-wide; improved; injury and repair; longitudinal analysis; molecular phenotype; novel; predictive modeling; programs; public health relevance; response; transcriptomics; treatment response; validation studies

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.

描述（由申请人提供）： 项目摘要 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，一个主要挑战是识别这些条件中存在的常见模式。目前，哮喘表型的定义仅限于有限的术语和不精确的临床范例，依赖于过敏史、发病年龄、肺功能和“严重程度”症状等特征。这些研究，包括哮喘簇的严重哮喘研究计划 (SARP) 特征，是有用的，但是由人口统计和生理变量的差异驱动的，这些指标与疾病的许多生物学方面相距甚远。4与这些方法相反，综合功能基因组学有可能在反映真实内表型的水平上定义哮喘内表型，这些内表型在机制上对哮喘很重要。 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，利用哮喘患者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 TEA 簇）。 TEA 簇 1 具有低水平的气道炎症和最可逆的气道阻塞； TEA 簇 2 具有中度气道炎症、可逆性气流阻塞和高痰液 IL-13 水平（Th2 簇）； TEA 簇 3 具有最高水平的气道炎症、最不可逆的气道阻塞（重塑簇）以及高水平的痰 YKL-40（一种几丁质酶样蛋白，我们已证明与重塑和严重哮喘相关）。此外，利用来自该队列的匹配血液基因表达数据，我们开发了一个使用 69 个基因的预测模型，可以以 85% 的准确度确定个体的痰 TEA 聚类分配。总而言之，这些数据表明转录组衍生的哮喘内表型与气道炎症、生理重塑和免疫表型相关细胞因子相关。在此应用中，将使用综合功能基因组学来评估 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反应。将评估 TEA 簇对其他肺部疾病的普遍性，以确定与 TEA 簇相关的基本表达网络。最终，这些研究将提高我们对疾病部位分子水平上哮喘异质性的理解，并识别具有相似基因网络调节的患者。这些结果将产生哮喘内表型的新分子诊断，可用于利用血液和痰基因​​表达对患者进行病理学和治疗研究的细分，并确定候选基因研究的新靶点。