R01HL151588

Imaging and Molecular Phenotyping of Cystic Fibrosis Lung Disease

Cystic Fibrosis (CF) is among the most common fatal genetic diseases in the U.S. It is characterized by progressive lung function loss and structural remodeling, which can ultimately lead to lung transplant or death. Although life expectancy in CF patients has increased due to improved treatments, pathological changes still occur within the first year of life. However, detecting these early changes has been challenging because conventional measures of lung function, such as spirometry, are lagging indicators and insensitive to early disease.

In contrast, ultra-short echo-time (UTE) and hyperpolarized (HP) 129XE MRI have shown promise in detecting pathology years before spirometry changes. Additionally, proteomic biomarkers from high-precision mass spectrometry (MS), when coupled with functional data (FD) analysis, have accurately forecasted 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 can 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.

The central hypothesis of this research is that image-guided proteomics can forecast pathophysiology before spirometric changes are observed. The rationale behind this hypothesis 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, enabling interventions before permanent lung damage occurs.

Guided by combined MRI and proteomic data and the utility of FD analysis to predict lung function decline, the central hypothesis will be tested by completing the following specific aims:

1) Validate predictive biomarkers in CF patients with normal spirometry but abnormal ventilation.
2) Determine the sensitivity and specificity of systemic biomarkers in predicting early structural remodeling in CF lung disease.
3) Perform clinical bronchoscopy to identify molecular signatures of irreversible lung remodeling.

The necessary MRI sequences and reconstruction pipeline have been developed to complete the work. For aims 1 and 2, MRI and MS proteomics have been used to identify key biomarkers to predict structural and functional abnormalities in CF. For aim 3, BAL proteomics has been used to identify molecular changes at the pathway level in CF patients.

This proposed research is innovative because it will use cutting-edge imaging to validate molecular tools to assess early lung disease. The results will be significant as they will produce an easily disseminated tool to predict permanent structural remodeling and irreversible functional losses. This work will have an immediate positive impact by developing and translating non-invasive 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.

Childrens Hospital Medical Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Cincinnati, Ohio 45229 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 438% from $729,164 to $3,919,631.