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.

项目摘要 慢性阻塞性肺疾病（COPD）是一种异质性疾病， 肺气肿和大小气道疾病。COPD异质性还表现在对以下因素的可变反应中： 治疗，包括吸入性皮质类固醇（ICS）。对于COPD结局的生物标志物存在未满足的需求。 我们的团队已经在遗传学研究中对2期（5年）访视时收集的血液样本进行了RNA测序。 COPD流行病学研究（COPD基因）。我们发现1型干扰素刺激的基因表达 全血中的特征与来自胸部计算机定量分析的气道测量相关。 断层扫描（CT）。总结这些基因表达的评分与肺功能减退有关 功能和COPD加重。干扰素基因评分和气道疾病之间的相关性是 在ICS用户中取消。我们的假设是，干扰素途径血液基因表达可以用来定义 以气道疾病为特征的COPD内型，将作为COPD的预测生物标志物 急性加重和进展，可以用ICS治疗靶向。我们将解决以下具体问题 目的：（1）气道干扰素预测急性加重和进展：使用COPD基因3期（10年） 临床和影像学数据，我们将使用干扰素气道基因标记作为生物标志物， 在有和没有COPD的受试者中急性加重和疾病进展的模型。述基因特征 预测将在其他COPD研究中得到验证。(2)COPD的气道干扰素内型：我们将进行 对COPDGene 3期访视的血液样本进行RNA测序，以检测稳定性与基因变化 表达特征和临床表型。为了确定肺组织相关的 血液基因表达，我们将分析RNA-seq数据切除肺样本的吸烟者和不吸烟者， 来自肺组织研究联盟（LTRC）的COPD，测试干扰素特征之间的关联 胸部CT扫描确定的气道疾病和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的关联是否 ICS患者气道疾病、急性加重和肺功能下降的特征和COPD表型发生改变 用户与非用户相比。我们将测量干扰素标记基因在先前的 在COPD基因受试者中完成ICS的12周临床试验，并测试ICS的使用是否影响干扰素- 刺激的基因表达模式。我们将重新分析临床试验，以测试干扰素信号是否 预测对ICS的反应。该提案将通过开发一种新的方法来补充COPDGene中正在进行的分析。 COPD结局的生物标志物和靶向ICS处方，可用于未来的药物基因组学 临床试验了解气道疾病干扰素基因特征可以指导未来的机制研究 并研究ICS以外的靶向治疗。