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: 10339411
• 负责人: ZACKARY I CLEVELAND
• 金额: $ 78.96万
• 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/10339411
• 关键词: Adolescence; Adult; Affect; Age; Algorithms; 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; 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; 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; Risk; 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; Work; X-Ray Computed Tomography; airway remodeling; base; 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; mass spectrometric imaging; molecular phenotype; novel; novel therapeutics; personalized approach; predictive marker; prevent; prognostic tool; prospective; pulmonary function; pulmonary function decline; reconstruction; 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.

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