Validating Quantitative Magnetic Resonance Imaging Biomarkers of Idiopathic Pulmonary Fibrosis

验证特发性肺纤维化的定量磁共振成像生物标志物

基本信息

批准号：
10322979
负责人：
ZACKARY I CLEVELAND
金额：
$ 75.11万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322979
关键词：
3-Dimensional Acute Age Alveolar Animal Model Animals Biological Biomechanics Biophysics Biopsy Cell Proliferation Chemicals Cicatrix Clinical Collagen Consensus Data Deposition Development Diagnosis Diffuse Diffusion Disease Progression Disease model Elements Environmental Exposure Epithelial Etiology Event Exhibits Extracellular Matrix FDA approved Failure Fibrosis Functional disorder Gases Goals Growth Health Health Care Costs Human Image Imaging technology Impairment Inflammation Inflammatory Injury Interstitial Lung Diseases Knowledge Lesion Life Link Lung Lung Compliance Lung diseases Magnetic Resonance Imaging Measures Mechanical Stress Mechanical ventilation Mechanics Mediator of activation protein Methods Microscopic Mission Modeling Molecular Monitor Morbidity - disease rate Mus Outcome Pathologic Pathology Patients Persons Pharmaceutical Preparations Physiology Pirfenidone Predisposition Process Profibrotic signal Property Public Health Pulmonary Fibrosis Pulmonary Pathology Pulmonary Surfactant-Associated Protein A Pulmonary Surfactant-Associated Protein C Radiation Relaxation Research Resolution Signal Transduction Structure of parenchyma of lung Surface Technology Testing Time Tissues Transforming Growth Factor alpha Transgenic Mice Transgenic Organisms Translating Treatment Efficacy United States National Institutes of Health Ventilator Water Work X-Ray Computed Tomography base clinical diagnosis clinically translatable contrast imaging density fibrotic lung functional decline idiopathic pulmonary fibrosis image processing image reconstruction imaging biomarker in vivo injured innovation insight lung imaging magnetic resonance imaging biomarker mortality mouse model mutant nintedanib normal aging novel strategies novel therapeutics overexpression pre-clinical preclinical study pulmonary function pulmonary function decline reconstruction temporal measurement therapeutic target therapeutically effective therapy development tool treatment response ventilation

项目摘要

Pulmonary fibrosis contributes to morbidity and mortality in a wide spectrum of lung diseases. While it can result from environmental exposures or acute injuries, the events that initiate lung fibrosis are typically unknown. This Idiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung disease, and it is associated with a post-diagnosis survival of only 3 years. Despite decades of research, only 2 drugs are FDA approved to treat IPF, and both merely slow its progression. Failure to produce treatments to reverse or halt disease progression can be attributed to poorly understood IPF etiology. In turn, poor understanding can be attributed to an inability to detect and quantify early fibrosis and relate regional parenchymal remodeling to the functional, biomechanical, and molecular processes that initiate fibrosis. Eliminating this gap will require significant scientific and technical developments involving both biologically realistic disease models and sensitive and specific imaging technology. The long-term goal of this research is to quantify early pulmonary remodeling and relate it to profibrotic mecha- nisms and emergent pathophysiology. Our objectives in this application are to 1) determine the biophysical origin of magnetic resonance imaging (MRI) relaxation in fibrotic lung tissue, 2) quantify alveolar ventilation, 3) apply these metrics to two realistic, transgenic mouse models, and 4) extend quantitative ventilation MRI to IPF pa- tients. Our central hypothesis is that relaxation and ventilation will correlate with ex vivo measures of fibrosis (e.g., regional collagen content) and provide sensitive, noninvasive methods of quantifying fibrosis progression in vivo. Our rationale is that imaging markers—once validated in animal models and IPF patients—can readily be applied in mechanistic preclinical studies and in assessing IPF progression and therapy efficacy. Guided by strong preliminary data and theoretical work describing MR signal dynamics in the lungs, our central hypothesis will be tested by completing the following three Specific Aims: 1) validate transverse relaxation as a marker of lung fibrosis; 2) quantify impaired ventilation with multi-breath HP 129Xe washout; and 3) demonstrate the sensi- tivity of HP 129Xe washout MRI to impaired ventilation in IPF patients. Under Aim 1, we have developed the MRI sequences and reconstruction pipeline needed to complete the work. Under Aim 2, we have constructed and validated a hyperpolarized gas and MRI-compatible ventilator and developed the image processing tools to quantify regional tissue density. Under Aim 3, we have pioneered the use of efficient 3D spiral MRI sequences and keyhole-based image reconstruction to produce high-quality, quantitative human lung images. The proposed research is innovative both biologically and technically, because it will develop and validate noninvasive, regional measures of biophysical tissue properties and ventilation. These results are significant, because they will provide a means of detecting early pro-fibrotic events and noninvasively quantifying lung fibrosis progression. This work will have an immediate positive impact by allowing potential lung fibrosis therapies to be assessed and will pro- vide tools that can be translated into clinical use for evaluating disease progression and therapy response.

肺纤维化有助于多种肺部疾病的发病率和死亡率。虽然可以结果从环境暴露或急性损伤中，启动肺纤维化的事件通常是未知的。这特发性肺纤维化（IPF）是间质性肺部疾病的最常见形式，它与诊断后的生存仅3年。尽管进行了数十年的研究，但只有2种药物被批准用于治疗 IPF，都只是放慢了其进展。未能产生逆转或停止疾病进展的治疗可以归因于不良理解的IPF病因。反过来，理解不佳可以归因于无法检测和量化早期纤维化和相关的区域副型重塑与功能，生物力学，和启动纤维化的分子过程。消除这一差距将需要大量的科学和技术发展涉及生物学现实的疾病模型和敏感和特定的成像技术。这项研究的长期目标是量化早期肺重塑，并将其与纤维化的机甲合成 NISM和新兴病理生理学。我们在本应用程序中的目标是1）确定生物物理起源纤维化肺组织中的磁共振成像（MRI）松弛，2）量化肺泡通气，3）应用这些指标是两个现实的转基因小鼠模型，4）将定量通气MRI扩展到IPF PA-- t。我们的中心假设是，放松和通风将与纤维化的离体测量相关（例如，区域胶原蛋白含量），并提供敏感的无创方法来量化纤维化进展体内。我们的理由是，在动物模型和IPF患者中验证的成像标记很容易应用于机械临床前研究，并评估IPF进展和治疗有效性。指导强大的初步数据和理论工作描述了肺中MR信号动力学，这是我们的中心假设将通过完成以下三个特定目标来测试：1）验证横向松弛作为标记肺纤维化； 2）用多呼吸的HP 129x擦洗来量化通风受损； 3）证明了感官 HP 129XE洗涤MRI的电位可损害IPF患者的通风。在AIM 1下，我们开发了MRI 完成工作所需的序列和重建管道。在AIM 2下，我们已经建造了验证了超极化的气体和与MRI兼容的呼吸机，并开发了图像处理工具量化区域组织密度。在AIM 3下，我们开创了有效的3D螺旋MRI序列的使用和基于钥匙孔的图像重建，以产生高质量的定量人肺图像。提议研究在生物学上和技术上都是创新的，因为它将发展和验证无创，区域性生物物理组织特性和通风的度量。这些结果很重要，因为它们将提供一种检测早期促纤维化事件和无创量化肺纤维化进展的方法。这项工作通过允许评估潜在的肺纤维化疗法，将产生直接的积极影响可以转化为评估疾病进展和治疗反应的临床用途的视频工具。