Hyperpolarized Xenon-129 MRI: a new multi-dimensional biomarker to determine pulmonary physiologic responses to COPD therapeutics

超极化 Xenon-129 MRI：一种新的多维生物标志物，用于确定慢性阻塞性肺病治疗的肺部生理反应

• 批准号: 10084708
• 负责人: Kun Qing
• 金额: $ 78.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084708
• 关键词: 3-Dimensional; Address; Adrenal Cortex Hormones; Affect; Aging; Agonist; Air Movements; Alveolar; Anatomy; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological Markers; Blood; Bronchodilation; Bronchodilator Agents; Cause of Death; Characteristics; Chemicals; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical assessments; Complex; Complex Mixtures; Correlation Studies; Data; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Disease; Disease Progression; Dropout; Erythrocytes; Exhibits; FDA approved; Fostering; Functional Imaging; Functional disorder; Future; Gases; High Resolution Computed Tomography; Human; Image; Imaging Techniques; Inflammation; Inhalation; Intervention; Life; Location; Lung; Magnetic Resonance Imaging; Maps; Measurement; Measures; Microscopic; Monitor; Muscarinic Antagonists; Outcome; Outcome Study; Pathogenesis; Pathologic; Patients; Penetrance; Pharmacology; Phase; Phenotype; Physiological; Physiology; Protocols documentation; Protons; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Research; Research Design; Resistance; Resolution; Respiratory physiology; Sensitivity and Specificity; Severities; Severity of illness; Smoker; Staging; Structure of parenchyma of lung; Surrogate Endpoint; Symptoms; Therapeutic; Tissues; United States; Xenon; airway obstruction; base; chest computed tomography; cigarette smoke; clinically relevant; cohort; disease phenotype; experience; fluticasone; high resolution imaging; imaging study; improved; in vivo; interest; lung volume; multimodality; non-invasive imaging; novel; novel marker; post intervention; potential biomarker; pulmonary function; recruit; response; specific biomarkers; therapy design; tool; treatment response; uptake; ventilation

Chronic Obstructive Pulmonary Disease (COPD) is diagnosed by pulmonary function test (PFT). PFT is commonly used to evaluate the severity and therapeutic response in COPD. However, complex mixture of COPD phenotypes requires a diagnostic tool with abilities to evaluate broader aspects of lung pathophysiology, and this is the primary reason why PFTs do not provide sufficient correlation with disease status and progression to serve as a reliable surrogate endpoint. What is needed is a quantitative and comprehensive set of COPD biomarkers that can provide phenotyping and staging of COPD, rapid assessment of response to a broad range of therapies, and tracking the progression of disease. The hope is that the hyperpolarized xenon magnetic resonance imaging (HXe MRI) could diagnose and intervene patients at the earliest stages of COPD, guide the selection of appropriate therapies, and extend life. In this proposal, two HXe MRI assessments will be performed. (1) A single sequence that combines a high-resolution image of inhaled HXe with a proton image acquired in the same breath-hold will provide the fraction of the lung volume with compromised airflow. (2) A new imaging protocol that exploits xenon's chemical shift sensitivity to the separate tissue compartments of the lung allows a detailed mapping of gas exchange through lung tissue and into the red blood cells. We hypothesize that these HXe MRI signatures will access physiologic information that were previously inaccessible by the conventional PFT and multimodality CT of chest, (MDCT). We also hypothesize that these imaging signatures will enhance our ability to evaluate COPD phenotypes and disease status better than the PFT and MDCT. Higher HXe MRI resolution based on the anatomy of the lung will further enhance the diagnostic sensitivity and specificity. In aim 1, we will perform a study of the correlation of imaging signatures of COPD with conventional assessments (PFT, MDCT and clinical outcomes). In aim 2, we will evaluate changes in the lung physiology of the patients with well-characterized COPD after being serially treated with three standard COPD therapies, long acting muscarinic antagonist (umeclidinium) and long acting beta-agonist (vilanterol) to improve ventilation, and inhaled corticosteroid (fluticasone) to potentially affect the inflammation in tissues. Our study design offers both cross-sectional and longitudinal information. Eighty treatment-naïve subjects will be evaluated at baseline, after two serial 30-day courses of umeclidinium/vilanterol and fluticasone. The 320 assessments, considered independently, will determine correlations between functional imaging signatures and conventional metrics which include PFT, MDCT, and clinical outcomes. Within-subject temporal alterations of the HXe MRI imaging will be evaluated as potential biomarkers to assess COPD phenotypes and disease status, both of which we anticipate to deepen our basic mechanisms contributing to the genesis of COPD and to promote development of new strategies to diagnose and treat COPD.

慢性阻塞性肺疾病（COPD）通过肺功能测试（PFT）诊断。 Pft是 通常用于评估COPD中的严重程度和治疗反应。但是，复杂的混合物 COPD表型需要具有能力的诊断工具，以评估肺病理生理学的更广泛方面， 这是PFTS不提供与疾病状况和疾病状况相关的主要原因 进展为可靠的替代端点。需要的是定量和全面的集合 COPD生物标志物可以提供COPD的表型和分期，快速评估对A的反应 广泛的疗法，并跟踪疾病的进展。希望是超极化氙 磁共振成像（HXE MRI）可以在COPD最早的阶段诊断和干预患者， 指导选择适当的疗法并延长寿命。在此提案中，两个HXE MRI评估将 被执行。 （1）将遗传性HXE的高分辨率图像与质子结合的单个序列 以相同的呼吸键获取的图像将为肺部体积的比例损害。 （2）一种新的成像协议，该方案利用了氙的化学移位灵敏度对单独的组织室 肺部允许通过肺组织和红细胞进行详细的气体交换图。我们 假设这些HXE MRI签名将访问以前的生理信息 传统的PFT和胸部多模式CT无法访问（MDCT）。我们还假设这些 成像特征将增强我们评估COPD表型和疾病状况的能力，而不是 PFT和MDCT。基于肺解剖结构的较高的HXE MRI分辨率将进一步增强 诊断灵敏度和特异性。在AIM 1中，我们将对成像特征的相关性进行研究 具有常规评估的COPD（PFT，MDCT和临床结果）。在AIM 2中，我们将评估 串行治疗后，特征良好COPD患者的肺部生理学变化 三种标准COPD疗法，长作用的毒蕈碱拮抗剂（Umeclidinium）和长作用β-激动剂 （vilanterol）改善通风和遗传性皮质类固醇（氟替卡酮），以可能影响炎症 在组织中。我们的研究设计提供横截面和纵向信息。八十次治疗 在两个序列的30天课程的Umeclidinium/vilanterol和 氟替卡酮。独立考虑的320个评估将确定功能之间的相关性 成像标志和常规指标，包括PFT，MDCT和临床结果。主题内 HXE MRI成像的暂时变化将被评估为评估COPD的潜在生物标志物 表型和疾病状况，我们预计这两者都可以加深我们的基本机制 COPD的起源并促进开发诊断和治疗COPD的新策略。

项目成果

Clinical Impact of Multidisciplinary Outpatient Care on Outcomes of Patients with COPD.

多学科门诊护理对慢性阻塞性肺病患者预后的临床影响。

• DOI: 10.2147/copd.s225156
• 发表时间: 2020
• 期刊: International journal of chronic obstructive pulmonary disease
• 影响因子: 2.8
• 作者: Mansoor,Sahar;Obaida,Zaid;Ballowe,Lorna;Campbell,AmandaR;Patrie,JamesT;Byrum,TimothyD;Shim,YunM
• 通讯作者: Shim,YunM

Evaluation of Regional Lung Function in Pulmonary Fibrosis with Xenon-129 MRI.

• DOI: 10.3390/tomography7030039
• 发表时间: 2021-09-15
• 期刊: Tomography (Ann Arbor, Mich.)
• 作者: Mata J;Guan S;Qing K;Tustison N;Shim Y;Mugler JP 3rd;Altes T;Huaromo J;Mehrad B
• 通讯作者: Mehrad B

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity.

• DOI: 10.1016/j.jaci.2015.07.037
• 发表时间: 2016-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Shipe R;Burdick MD;Strieter BA;Liu L;Shim YM;Sung SS;Teague WG;Mehrad B;Strieter RM;Rose CE Jr
• 通讯作者: Rose CE Jr

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice.

• DOI: 10.1038/s41467-021-25590-8
• 发表时间: 2021-09-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bisht K;Okojie KA;Sharma K;Lentferink DH;Sun YY;Chen HR;Uweru JO;Amancherla S;Calcuttawala Z;Campos-Salazar AB;Corliss B;Jabbour L;Benderoth J;Friestad B;Mills WA 3rd;Isakson BE;Tremblay MÈ;Kuan CY;Eyo UB
• 通讯作者: Eyo UB

Measures of ventilation heterogeneity mapped with hyperpolarized helium-3 MRI demonstrate a T2-high phenotype in asthma.

• DOI: 10.1002/ppul.25303
• 发表时间: 2021-06
• 期刊: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Gerald Teague W;Mata J;Qing K;Tustison NJ;Mugler JP;Meyer CH;de Lange EE;Shim YM;Wavell K;Altes TA
• 通讯作者: Altes TA