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The role of mucus and pulmonary surface interactions in lung defense

Award Number: R01HL125280
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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The role of mucus and pulmonary surface interactions in lung defense - The mucus clearance system of the lung represents a key innate immune system that protects the airway surface against constant exposure to inhaled infectious and noxious particles. However, abnormal clearance of mucus by cilia beating and cough represents a significant contributor to the pathogenesis in so-called muco-obstructive lung diseases, including cystic fibrosis, asthma, and chronic bronchitis. Despite the role that reduced clearance of mucus plays in patients with muco-obstructive lung diseases, there are large gaps in our knowledge of how abnormal mucus produces such mucostasis. In order to understand the root causes of the pathology and develop effective therapies to treat such diseases, it is necessary to understand the fundamental mechanisms involved in regulating mucus clearance in health and understand how is it affected by disease. Therefore, the goal of this project is to answer a number of unresolved questions regarding the mucus clearance system. In the first specific aim, we seek to understand what role airway mucins, the large biopolymers which give mucus its gel-like properties, play in facilitating efficient mucus clearance in health. Here, we will use novel in vitro cilia- and cough- mediated clearance assays to test the hypothesis that airway mucins are vital for efficient mucus clearance out of the lung, as a result of interactions between mucins and the airway cell surface. Studies will also identify which mucin domains are involved in this interaction. In the second aim, we will address another outstanding question of whether higher-order multimerization of mucins, to very long polymers, is required for efficient mucus transport. This question has clinical relevance as disulfide bond reducing agents, which “cleave” long-chain mucins and reduce the elastic properties of mucus, have been proposed as a mucolytic therapy for lung diseases. In this aim, we will test the hypothesis that mucin polymerization is required for efficient cilia- and cough-mediated mucus transport by facilitating the clearance of mucus transport across regions of the airways with poor cilia beat coordination or devoid of ciliated cells, as a result of airway damage associated with gastric aspiration, cigarette smoking, and certain viral infections. In the third aim, we will test the hypothesis that mucin/cell surface interactions are abnormal in diseases associated with hyperproduction of secreted MUC5AC mucin, as a result of Th2 cytokine signaling. Specifically, we will test the hypothesis that chronic IL-13-mediated increases in MUC5AC expression can increase the strength of the cilia-mucus interactions, generating a more adherent, hard to clear, mucus layer. To assess the impact of disease-related increases in MUC5AC expression we will utilize novel mucus adhesion and friction testing devices which quantifies the adherence of mucus to the airway surface and resistance of mucus propulsion. The testing of these hypotheses will be critical to address many gaps in our knowledge about mucus clearance system functions in health, why it is dysfunctional in disease, and to identify targets for approaches to restore/accelerate mucus clearance in persons with muco-obstructive 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: 2023 ( Subtotal = $388,750 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	8	6/16/2023	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2022 ( Subtotal = $388,750 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	7	6/30/2022	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2021 ( Subtotal = $388,750 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	002	6	8/6/2021	NON-COMPETING CONTINUATION	$388,750
2021	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	001	5	3/10/2021	COMPETING CONTINUATION	$5,148
2021	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	4	3/10/2021	NON-COMPETING CONTINUATION	-$5,148
														Subtotal = $388,750

Issue Date FY: 2020 ( Subtotal = $388,750 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	5	6/26/2020	COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2018 ( Subtotal = $377,740 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	4	6/13/2018	NON-COMPETING CONTINUATION	$377,740
														Subtotal = $377,740

Issue Date FY: 2017 ( Subtotal = $377,740 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	3	6/21/2017	NON-COMPETING CONTINUATION	$377,740
														Subtotal = $377,740

Issue Date FY: 2016 ( Subtotal = $377,740 )
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	2	6/27/2016	NON-COMPETING CONTINUATION	$377,740
														Subtotal = $377,740

Issue Date FY: 2015 ( Subtotal = $377,740 )
2015	2015	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	1	7/3/2015	NEW	$377,740
														Subtotal = $377,740

Grand Total All Awards = $3,065,960

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The role of mucus and pulmonary surface interactions in lung defense

Award Number: R01HL125280

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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