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Imaging and Molecular Phenotyping of Cystic Fibrosis Lung Disease

Award Number: R01HL151588
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/03/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Imaging and Molecular Phenotyping of Cystic Fibrosis Lung Disease - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $710,193 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	5	1/13/2025	NON-COMPETING CONTINUATION	$710,193
														Subtotal = $710,193

Issue Date FY: 2024 ( Subtotal = $767,868 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	4	1/8/2024	NON-COMPETING CONTINUATION	$705,185
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	4	6/20/2024	NON-COMPETING CONTINUATION	$62,683
														Subtotal = $767,868

Issue Date FY: 2023 ( Subtotal = $783,539 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	3	3/8/2023	NON-COMPETING CONTINUATION	$783,539
														Subtotal = $783,539

Issue Date FY: 2022 ( Subtotal = $789,560 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$78,957
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	2	1/10/2022	NON-COMPETING CONTINUATION	$710,603
														Subtotal = $789,560

Issue Date FY: 2021 ( Subtotal = $789,560 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	000	1	2/3/2021	NEW	$729,164
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Lung Diseases Research	001	1	8/4/2021	NEW	$60,396
														Subtotal = $789,560

Grand Total All Awards = $3,840,720

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Imaging and Molecular Phenotyping of Cystic Fibrosis Lung Disease

Award Number: R01HL151588

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/03/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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