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性遗传病之一，涉及进行性肺部疾病 功能丧失和结构重塑，导致肺移植或死亡。尽管慢性阻塞性肺疾病患者的预期寿命 虽然由于治疗方法的改进而有所增加，但在出生后的第一年内仍会出现病变。一直以来 很难检测到这些早期变化，因为肺功能的常规测量，例如肺活量测定法(例如， 1秒用力呼气量(FEV1)是滞后指标，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之前数年发现病理。另外-- 可选地，来自高精度质谱学(MS)的蛋白质组生物标志物，当与基于建模的 在功能数据(FD)分析中，准确预测了CF肺部疾病的进展。然而，这些生物标志物 仅在有既往疾病的患者中得到验证。这项研究的长期目标是验证 早期肺部疾病中检测和预测肺功能下降和结构重塑的蛋白质组学标志物。 该应用程序目的是使用最先进的HP 129Xe和UTE MRI来验证蛋白质组标记 在早期的CF.这将通过血清和临床获得的支气管肺泡灌洗(BAL)来完成。 已知肺部病理的CF患者的体液。我们的中心假设是图像引导蛋白质组学可以 在观察肺活量变化之前预测病理生理学。我们的理由是，虽然129Xe和UTE 核磁共振成像目前仅限于专门的中心，MS蛋白质组学可以在容易获得的临床上进行 样本，并与FD分析转换为一种易于传播的预测即将到来的肺部疾病的工具 因此，在永久性肺损伤发生之前进行干预是可行的。由联合核磁共振引导 以及蛋白质组学数据和FD分析预测肺功能下降的效用，我们的中心假设将是 通过完成以下特定目标进行测试：1)验证我们的预测生物标记物在CF患者中的正常 肺活量测定，但换气异常；2)确定系统生物标志物的敏感性和特异性 判断慢性肺病的早期结构重建；3)临床支气管镜检查以确定分子 不可逆肺重塑的征兆。我们已经开发了MRI序列和重建流水线 来完成这项工作。对于AIMS 1和AIMS 2，我们使用MRI和MS蛋白质组学来确定关键的生物标志物 目的：预测CF的结构和功能异常。对于Aim 3，我们使用BAL蛋白质组学来鉴定 慢性萎缩性胃炎患者途径水平的分子变化这项拟议的研究具有创新性，因为它将使用 尖端成像，以验证评估早期肺部疾病的分子工具。这些结果将是重要的， 因为它们将产生一个容易传播的工具来预测永久性的结构重塑和不可逆转- 可恢复的功能损失。这项工作将通过开发和翻译非INVERA-INVERA产生直接的积极影响 严格的测试，以识别肺损伤的高风险的CF患者，并在不可逆转的变化发生之前进行干预。它 还将提供一个独特的平台，以评估广泛的肺部疾病的病理进展。