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

• 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
• 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

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.

肺纤维化导致多种肺部疾病的发病率和死亡率。虽然它可能会导致 从环境暴露或急性损伤来看，引发肺纤维化的事件通常是未知的。这 特发性肺纤维化(IPF)是间质性肺疾病最常见的形式，它与 确诊后仅存活3年。尽管经过几十年的研究，FDA只批准了两种药物用于治疗 IPF，两者都只是减缓了它的进展。未能研制出逆转或阻止疾病进展的治疗方法 可归因于对IPF病因知之甚少。反过来，理解能力差可以归因于无能。 检测和量化早期纤维化，并将局部实质重塑与功能、生物力学、 以及引发纤维化的分子过程。消除这一差距将需要大量的科学和技术 包括生物学上逼真的疾病模型和敏感和特异的成像技术的发展。 这项研究的长期目标是量化早期的肺重构，并将其与促纤维化机制联系起来。 神经症和紧急病理生理学。我们在这项申请中的目标是1)确定生物物理起源 磁共振成像(MRI)对纤维化肺组织的松弛作用，2)定量肺泡通气量，3)应用 这些指标适用于两个真实的转基因小鼠模型，以及4)将定量通风MRI扩展到IPF-PA。 蒂恩斯。我们的中心假设是，放松和换气将与体外纤维化的测量相关。 (例如，局部胶原含量)，并提供对纤维化进展进行量化的敏感、非侵入性方法 在活体内。我们的理论基础是，成像标记--一旦在动物模型和IPF患者中得到验证--很容易 可应用于机械性临床前研究以及评估IPF进展和治疗效果。指导原则 描述肺部磁共振信号动力学的强有力的初步数据和理论工作，这是我们的中心假设 将通过完成以下三个具体目标进行测试：1)验证横向放松作为 肺纤维化；2)通过多次呼吸HP 129Xe冲洗来量化换气障碍；以及3)显示 HP-129Xe洗脱磁共振对特发性肺功能不全患者呼吸功能障碍的诊断价值在目标1下，我们开发了核磁共振 完成工作所需的序列和重建流水线。在目标2下，我们已经建造和 验证了超极化气体和MRI兼容的呼吸机，并开发了图像处理工具以 量化区域组织密度。在目标3下，我们率先使用了高效的3D螺旋MRI序列 和基于钥匙孔的图像重建，以产生高质量、定量的人类肺部图像。建议数 研究在生物学和技术上都是创新的，因为它将开发和验证非侵入性的、区域性的 生物物理组织特性和通风的测量。这些结果意义重大，因为它们将提供 一种检测早期促纤维化事件和非侵入性量化肺纤维化进展的方法。这部作品 将立即产生积极影响，使潜在的肺纤维化治疗得到评估，并将有利于- VIDE工具，可转化为临床使用，用于评估疾病进展和治疗反应。