Imaging and Molecular Phenotyping of Cystic Fibrosis Lung Disease

囊性纤维化肺病的影像学和分子表型

• 批准号: 10548868
• 负责人: ZACKARY I CLEVELAND
• 金额: $ 78.35万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-03 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548868
• 关键词: Acceleration; Adolescence; Adult; Affect; Age; Anti-Inflammatory Agents; Asthma; Biological Markers; Blood; Blood Proteins; Blood specimen; Bronchi; Bronchiectasis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cessation of life; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Trials; Coupled; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Data Analyses; Demographic Factors; Diagnosis; Disease; Disease Progression; Early Diagnosis; Functional disorder; Future; Genetic Diseases; Goals; Health; Heterogeneity; Image; Impairment; Individual; Infection; Inflammation; Intervention; Investigation; Irrigation; Knowledge; Life; Life Expectancy; Liquid Chromatography; Liquid substance; Lung; Lung Transplantation; Lung diseases; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Methods; Mission; Modeling; Molecular; Molecular Profiling; Monitor; Mucous body substance; Mutation; Nature; Outcome; Outcome Measure; Pathologic; Pathology; Pathway interactions; Patients; Plasma; Proteomics; Public Health; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Pathology; Radiation; Reaction; Regulator Genes; Research; Resolution; Respiratory Failure; Respiratory Tract Infections; Scanning; Sensitivity and Specificity; Serum; Severity of illness; Specialized Center; Specimen; Spirometry; Structural defect; Technology; Testing; Time; Translating; Translations; United States; United States National Institutes of Health; Visualization; Work; X-Ray Computed Tomography; airway remodeling; children with cystic fibrosis; cohort; cystic fibrosis patients; early cystic fibrosis; evidence base; functional decline; functional loss; high risk; image guided; imaging modality; improved; individualized medicine; innovation; loss of function; lung injury; molecular phenotype; novel; novel therapeutics; personalized approach; predictive marker; prevent; prognostic tool; prospective; pulmonary function; pulmonary function decline; reconstruction; risk prediction model; specific biomarkers; tandem mass spectrometry; tool; ventilation

Cystic fibrosis (CF) is among the most common fatal genetic diseases in the U.S. and involves progressive lung function loss and structural remodeling, leading to lung transplant or death. Though life expectancy in CF patients has increased due to improved treatments, pathological changes still occur within the first year of life. It has been difficult to detect these early changes, because conventional measures of lung function such as spirometry (e.g., forced expiratory volume in 1 second, FEV1) are lagging indicators and insensitive to early disease. In contrast, ultra-short echo-time (UTE) and hyperpolarized (HP) 129Xe MRI can detect pathology years before FEV1. Addi- tionally, proteomic biomarkers from high-precisions mass spectrometry (MS), when coupled with modeling based on Functional Data (FD) analysis, accurately forecast CF lung disease progression. However, these biomarkers have only been validated in patients with established disease. The long-term goal of this research is to validate proteomic markers that detect and predict lung function decline and structural remodeling in early lung disease. The objective of this application is to use state-of-the-art HP 129Xe and UTE MRI to validate proteomic markers in early CF. This will be accomplished using blood serum and clinically obtained bronchoalveolar lavage (BAL) fluid from CF patients with known lung pathology. Our central hypothesis is that image-guided proteomics can forecast pathophysiology before spirometric changes are observed. Our rationale is that, while 129Xe and UTE MRI are currently limited to specialized centers, MS proteomics can be performed on readily obtained clinical specimens, and translated with FD analysis into an easily disseminated tool to predict impending lung disease progression, and thus enable interventions before permanent lung damage occurs. Guided by combined MRI and proteomic data and the utility of FD analysis to predict lung function decline, our central hypothesis will be tested by completing the following Specific Aims: 1) Validate our predictive biomarkers in CF patients with normal spirometry but abnormal ventilation; 2) determine the sensitivity and specificity of systemic biomarkers in pre- dicting early structural re-modeling in CF lung disease; and 3) perform clinical bronchoscopy to identify molecular signatures of irreversible lung remodeling. We have developed the MRI sequences and reconstruction pipeline needed to complete the work. For Aims 1 & 2, we have used MRI and MS proteomics to identify key biomarkers to predict structural and functional abnormalities in CF. For Aim 3, we have used BAL proteomics to identify molecular changes at the pathway level in CF patients. The proposed research is innovative, because it will use cutting-edge imaging to validate molecular tools to assess early lung disease. These results will be significant, because they will produce an easily disseminated tool to predict permanent structural remodelling and irreversi- ble functional losses. This work will have an immediate positive impact by developing and translating non-inva- sive tests to identify CF patients at high risk of lung damage and intervene before irreversible changes occur. It will also provide a unique platform to assess pathological progression in a wide range of lung diseases.

囊性纤维化（CF）是美国最常见的致命遗传疾病之一，涉及进行性肺 功能损失和结构重塑，导致肺移植或死亡。尽管CF患者的预期寿命 由于治疗的改善而增加了，病理变化仍在生命的第一年内发生。它一直 很难检测到这些早期变化，因为肺功能等常规测量（例如 在1秒内强制呼气量，FEV1）是滞后的指标，对早期疾病不敏感。相比之下， 超短回声时间（UTE）和超极化（HP）129XE MRI可以在FEV1之前检测病理学几年。添加 当与基于建模的基于建模时，从高预测质谱法（MS）中的蛋白质组学生物标志物（MS） 在功能数据（FD）分析上，准确预测CF肺部疾病进展。但是，这些生物标志物 仅在已建立疾病的患者中得到了验证。这项研究的长期目标是验证 检测和预测早期肺部疾病中肺功能下降和结构重塑的蛋白质组学标记。 该应用的目的是使用最先进的HP 129XE和UTE MRI来验证蛋白质组学标记 在早期CF中。这将使用血清和临床获得的支气管肺泡灌洗（BAL）来完成 来自已知肺病理学的CF患者的液体。我们的中心假设是图像引导的蛋白质组学可以 在观察到肺活量测定变化之前的预测病理生理学。我们的理由是，而129xe和ute MRI目前仅限于专业中心，MS蛋白质组学可以在容易获得的临床上进行 标本，并通过FD分析转换为一种易于传播的工具，以预测即将发生的肺部疾病 进展，从而在永久性肺损伤发生之前实现干预措施。由联合MRI指导 以及蛋白质组学数据以及FD分析预测肺功能下降的实用性，我们的中心假设将是 通过完成以下特定目的测试：1）验证正常CF患者的预测生物标志物 肺活量测定法但通气异常； 2）确定全身生物标志物在前的敏感性和特异性 在CF肺部疾病中决定早期结构重新模拟； 3）进行临床支气管镜检查以鉴定分子 不可逆的肺重塑的签名。我们已经开发了MRI序列和重建管道 需要完成工作。对于目标1和2，我们使用MRI和MS蛋白质组学来识别关键生物标志物 预测CF的结构和功能异常。对于AIM 3，我们使用Bal蛋白质组学来识别 CF患者的途径水平的分子变化。拟议的研究具有创新性，因为它将使用 尖端成像以验证分子工具以评估早期肺部疾病。这些结果将很重要， 因为它们会产生一种易于传播工具，以预测永久的结构重塑和不转换 功能损失。这项工作将通过开发和翻译非Inva-将立即产生积极的影响 SIVE测试以识别出在不可逆变化之前肺部损伤高风险和干预的CF患者。它 还将提供一个独特的平台来评估多种肺部疾病的病理发展。