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

定义气道疾病、COPD 恶化和治疗反应的基因表达特征

• 批准号: 10733573
• 负责人: CRAIG P HERSH
• 金额: $ 83.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733573
• 关键词: Acute; Adrenal Cortex Hormones; Affect; Airway Disease; Biological Markers; Blood; Blood specimen; COVID-19 pandemic; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Trials; Complement; Data; Data Set; Diagnosis; Disease; Disease Outcome; Disease Progression; Eosinophilia; Frequencies; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Guidelines; Image; Immune response; Impairment; Inflammation; Inhalation; Inhalators; Interferon alpha; Interferon-beta; Interferons; Lung; Measures; Morbidity - disease rate; Pathway interactions; Patients; Peripheral; Pharmacogenomics; Phase; Phenotype; Pulmonary Emphysema; Pulmonary function tests; Recommendation; Research; Resected; Resolution; Respiratory Signs and Symptoms; Sampling; Scanning; Smoker; Steroids; Structure of parenchyma of lung; Subgroup; Testing; Time; Viral; Virus Diseases; Visit; Visualization; Whole Blood; airway obstruction; chest computed tomography; cigarette smoking; clinical phenotype; disease classification; disease heterogeneity; disease natural history; disease phenotype; disorder subtype; eosinophil; experience; genetic epidemiology; genetic signature; insight; mortality; outcome prediction; phase 3 study; precision medicine; predicting response; predictive marker; predictive modeling; predictive signature; pulmonary function; pulmonary function decline; response; small airways disease; stability testing; targeted treatment; trait; transcriptome sequencing; treatment response; trend

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.

项目概要 慢性阻塞性肺疾病 (COPD) 是一种异质性疾病，其影响因素各不相同 肺气肿和大小气道疾病。 COPD 的异质性还体现在对以下因素的不同反应上： 治疗，包括吸入皮质类固醇（ICS）。对于慢性阻塞性肺病结局的生物标志物的需求尚未得到满足。 我们的团队领导了对遗传研究中第 2 阶段（5 年）访视时收集的血液样本进行 RNA 测序。 慢性阻塞性肺病流行病学研究 (COPDGene)。我们发现 1 型干扰素刺激的基因表达 全血中的特征与胸部计算的定量分析中的气道测量值相关 断层扫描（CT）。总结这些基因表达的评分与肺功能减少相关 功能和 COPD 恶化。干扰素基因评分与气道疾病之间的关联为 在 ICS 用户中废除。我们的假设是干扰素途径血液基因表达可用于定义 以气道疾病为特征的 COPD 内型，将作为 COPD 的预测生物标志物 恶化和进展，并且可以通过 ICS 治疗来靶向。我们将解决以下具体问题 目标：(1) 急性加重和进展的气道干扰素预测因子：使用 COPDGene 第 3 期（10 年） 临床和影像数据，我们将使用干扰素气道基因特征作为生物标志物来开发预测 患有和不患有慢性阻塞性肺病的受试者的急性加重和疾病进展模型。基因签名 预测将在其他慢性阻塞性肺病研究中得到验证。 (2) COPD气道干扰素内型：我们将进行 对 COPDGene 第 3 期访问的血液样本进行 RNA 测序，以测试基因的稳定性与变化 五年间隔内的表达特征和临床表型。确定肺组织的相关性 血液基因表达，我们将分析吸烟者和不吸烟者的切除肺样本中的RNA-seq数据 肺组织研究联盟 (LTRC) 的 COPD，测试干扰素特征之间的关联 胸部 CT 扫描定义的气道疾病和 COPD 表型的基因。 (3) 吸入反应 皮质类固醇：在 COPDGene 和 LTRC 中，我们将测试干扰素基因之间是否存在关联 ICS 中气道疾病、恶化和肺功能下降的特征和 COPD 表型发生改变 用户与非用户的比较。我们将测量先前的干扰素特征基因的表达 在 COPDGene 受试者中完成了 ICS 的 12 周临床试验，并测试 ICS 的使用是否会影响干扰素 刺激的基因表达模式。我们将重新分析临床试验，以测试干扰素特征是否 预测对 ICS 的反应。该提案将通过开发一种方法来补充 COPDGene 中正在进行的分析 COPD 结果的生物标志物和有针对性的 ICS 处方，可用于未来的药物基因组学 临床试验。了解气道疾病干扰素基因特征可以指导未来的机制研究 以及 ICS 以外的靶向治疗研究。