Defining a gene expression signature of airway disease, COPD exacerbations, and response to treatment

项目总结 慢性阻塞性肺疾病(COPD)是一种异质性疾病，其发病机制各不相同 肺气肿和大小呼吸道疾病。慢性阻塞性肺疾病的异质性也表现在对 治疗，包括吸入皮质类固醇(ICS)。对COPD预后的生物标记物的需求尚未得到满足。 我们小组已经领导了对在遗传学第二阶段(5年)访问时收集的血液样本的RNA测序 慢性阻塞性肺疾病流行病学研究(COPD基因)。我们发现一种1型干扰素刺激的基因表达 全血中的信号与胸部计算机定量分析中的呼吸道测量有关 断层扫描(CT)。总结这些基因表达的分数与肺减少有关。 功能和慢性阻塞性肺疾病恶化。干扰素基因评分与呼吸道疾病之间的关联是 在ICS用户中被废除。我们的假设是干扰素途径的血液基因表达可以用来定义 一种以呼吸道疾病为特征的COPD内型，将作为COPD的预测生物标志物 病情恶化和进展，并可通过ICS治疗进行靶向治疗。我们将解决以下具体问题 目的：(1)呼吸道-干扰素预测病情恶化和进展：使用COPD基因阶段3(10年) 临床和影像数据，我们将使用干扰素呼吸道基因签名作为生物标志物来开发预测 有无慢性阻塞性肺病患者的急性加重和疾病进展模型。基因签名 预测将在其他COPD研究中得到验证。(2)COPD的呼吸道干扰素内型：我们将进行 COPD基因第3期来访的血液样本中的RNA测序以测试基因的稳定性和变化 五年间的表达特征和临床表型。以确定肺组织与 血液基因表达，我们将分析吸烟者和非吸烟者切除的肺样本中的rna-seq数据。 来自肺组织研究联盟(LTRC)的COPD，干扰素签名之间的关联测试 胸部CT扫描的基因定义了呼吸道疾病和COPD表型。(3)吸入后的反应 皮质类固醇激素：在COPD基因和LTRC中，我们将测试干扰素基因与 ICS患者呼吸道疾病、恶化和肺功能下降的特征和COPD表型改变 用户与非用户的比较。我们将测量干扰素签名基因在以前的 在COPD基因受试者中完成了ICS的12周临床试验，并测试ICS的使用是否影响干扰素- 刺激基因表达模式。我们将重新分析临床试验，以测试干扰素签名是否 预测对ICS的反应。这项建议将通过开发一种 COPD预后的生物标志物和靶向ICS处方，可用于未来的药物基因组学 临床试验。了解呼吸道疾病干扰素的基因特征可以指导未来的机制研究 以及研究ICS以外的靶向治疗。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, with varying contributions of emphysema and large and small airway disease. COPD heterogeneity is also manifest in variable responses to treatments, including inhaled corticosteroids (ICS). There is an unmet need for biomarkers for COPD outcomes. Our group has led RNA-sequencing on blood samples collected at the Phase 2 (5 year) visit in the Genetic Epidemiology of COPD Study (COPDGene). We found that a type 1 interferon-stimulated gene expression signature in whole blood was associated with airway measures from quantitative analysis of chest computed tomography (CT) scans. A score summarizing the expression of these genes was associated with reduced lung function and COPD exacerbations. The association between the interferon gene score and airway disease was abolished in ICS users. Our hypothesis is that interferon pathway blood gene expression could be used to define an endotype of COPD characterized by airway disease, which will serve as a predictive biomarker for COPD exacerbations and progression and can be targeted with ICS therapy. We will address the following Specific Aims: (1) Airway-interferon predictor of exacerbations and progression: Using COPDGene Phase 3 (10 year) clinical and imaging data, we will use the interferon airway gene signature as a biomarker to develop prediction models for acute exacerbations and disease progression in subjects with and without COPD. The gene signature prediction will be validated in additional COPD studies. (2) Airway-interferon endotype of COPD: We will perform RNA-sequencing in blood samples from the COPDGene Phase 3 visit to test for stability vs. change of gene expression signatures and clinical phenotypes over a five-year interval. To identify lung tissue correlates of the blood gene expression, we will analyze RNA-seq data in resected lung samples from smokers with and without COPD from the Lung Tissue Research Consortium (LTRC), testing for associations between interferon signature genes with chest CT scan-defined airway disease and COPD phenotypes. (3) Response to inhaled corticosteroids: In COPDGene and LTRC, we will test whether the associations between the interferon gene signature and COPD phenotypes of airway disease, exacerbations, and lung function decline are altered in ICS users compared to non-users. We will measure expression of interferon signature genes in a previously completed 12-week clinical trial of ICS in COPDGene subjects, and test whether ICS use affects the interferon- stimulated gene expression pattern. We will re-analyze the clinical trial to test whether the interferon signature predicts response to ICS. This proposal will complement the ongoing analyses in COPDGene by developing a biomarker for COPD outcomes and targeted ICS prescription, which can be used for a future pharmacogenomics clinical trial. Understanding the airway disease interferon gene signature can guide future mechanistic studies and research into targeted therapies beyond ICS.