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The Role of Airway Mucus in Infection and Inflammation

Award Number: R01HL153079
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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The Role of Airway Mucus in Infection and Inflammation - Project Summary / Abstract Abnormal mucociliary clearance (MCC) is a critical component of cystic fibrosis (CF) lung disease, and is postulated to contribute to the high incidence of chronic pulmonary infections in this patient population; in turn the presence of chronic infection is thought to worsen the MCC defect, creating a cycle of mucus obstruction, infection, and inflammation that is difficult to interrupt or reverse. However, the mechanisms and interactions responsible for this phenomenon are not well understood. New animal models, such as the CF rat, developed at our institution, have been useful in identification of key factors that lead to chronic infection with the pathogen Pseudomonas aeruginosa in the CF airway. This animal model develops the MCC defect progressively, providing a model with which to study patients with early disease as well as late disease. In this model of CF, mucus must be abnormal before exposure to Pseudomonas aeruginosa to convert the infection to a chronic phenotype. CF rats exposed before the mucus abnormality develops are able to clear the infection. A new rat model harboring a humanized G551D-CFTR genomic insert respond to FDA-approved CFTR modulators that treat the fundamental defect of CF disease. Using the innovative Micro-Optical Coherence Tomography (µOCT), a high-resolution reflectance imaging modality that can simultaneously and non-invasively evaluate airway hydration, ciliary beating and mucus transport and viscosity in situ, we can analyze aspects of the mucus defect in both the CF rat model before and after infection, with or without CFTR modulators. Using these tools, this proposal will seek to investigate the mechanisms that cause patients with CF to transition acute infections into chronic ones, with the following independent but complimentary aims: 1. Determine if Muc5b is the specific component of mucus that promotes chronic Pseudomonas aeruginosa infection. 2. Determine if inflammation is necessary and sufficient to accelerate the mucus defect, predisposing the airway to chronic P. aeruginosa infection. 3. Determine if new highly effective CFTR modulators promote clearance of P. aeruginosa by normalizing abnormal mucus in the airway. This proposal will determine the early events that lead to infection and progression in CF pulmonary disease and how this relates to the conversion of P. aeruginosa from intermittent to chronic in this patient population, using a highly relevant animal model. The studies will provide new fundamental observations that will inform our understanding of the CF respiratory pathology and help identify robust therapeutic targets suitable for intervention.


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 = $445,370 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	5	5/15/2025	NON-COMPETING CONTINUATION	$445,370
														Subtotal = $445,370

Issue Date FY: 2024 ( Subtotal = $436,463 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	5/20/2024	NON-COMPETING CONTINUATION	$436,463
														Subtotal = $436,463

Issue Date FY: 2023 ( Subtotal = $445,370 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	3	5/12/2023	NON-COMPETING CONTINUATION	$445,370
														Subtotal = $445,370

Issue Date FY: 2022 ( Subtotal = $445,370 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	2	5/13/2022	NON-COMPETING CONTINUATION	$445,370
														Subtotal = $445,370

Issue Date FY: 2021 ( Subtotal = $445,370 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	1	6/14/2021	NEW	$44,537
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	5/27/2021	NEW	$400,833
														Subtotal = $445,370

Grand Total All Awards = $2,217,943

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The Role of Airway Mucus in Infection and Inflammation

Award Number: R01HL153079

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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