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Controlling the core airway mucin secretion machinery to prevent pathophysiology

Award Number: R01HL129795
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Controlling the core airway mucin secretion machinery to prevent pathophysiology - Mucus forms an essential barrier that protects the lungs from inhaled particles, pathogens and chemicals. These toxicants are entrapped in mucus, then swept out of the lungs by ciliary action. Paradoxically however, mucus dysfunction contributes to the pathobiology of all of the common diseases of the airways, including asthma, cystic fibrosis and COPD, as well as to interstitial lung diseases. Mucin glycoproteins are the principal macromolecular component of mucus, responsible for its structure as a semi-solid gel by interacting with several hundred-fold their mass of water. Mucins are secreted both at a low baseline rate and a high stimulated rate. A common feature of airway mucus dysfunction is the rapid secretion of hyperproduced mucins into the airway lumen, forming mucus that is excessively viscoelastic and cannot be cleared by ciliary action. This impedes airflow and provides a protected environment for microbial growth While the control of mucin production and hydration have been studied intensively, the mechanism of secretion is incompletely understood. Exocytosis in all eukaryotes is mediated by the cooperative interactions of a SNARE complex and an SM scaffolding protein, which are the core exocytic machinery. Our studies show that for some components of this machinery, different isoforms function in basal versus stimulated mucin secretion. Our central hypothesis is that two different VAMP proteins define two distinct classes of mucin secretory granules, associated with distinct secretory function and with distinct trafficking regulatory proteins. Aim 1. Determine the roles of VAMP3 and VAMP8 in defining two distinct structural and functional classes of mucin secretory granules. Aim 2. Determine how mucin granules are assembled, from their exit from the trans-Golgi network, through homotypic fusion, to form two classes of mature fusion-ready granules. Aim 3. Determine the physiological and pathophysiological consequences of manipulating the traffic of the two mucin granule classes. Completion of these aims will provide fundamental understanding of the mucin secretory mechanism, and will apply that knowledge to test translational strategies for mitigating mucus dysfunction while preserving its protective benefits.


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: 2024 ( Subtotal = -$3 )
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	8	8/6/2024	NON-COMPETING CONTINUATION	-$3
														Subtotal = -$3

Issue Date FY: 2023 ( Subtotal = $537,168 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	8	3/28/2023	NON-COMPETING CONTINUATION	$537,168
														Subtotal = $537,168

Issue Date FY: 2022 ( Subtotal = $537,168 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	001	7	6/15/2022	NON-COMPETING CONTINUATION	$53,717
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	7	3/16/2022	NON-COMPETING CONTINUATION	$483,451
														Subtotal = $537,168

Issue Date FY: 2021 ( Subtotal = $537,168 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	6	3/16/2021	NON-COMPETING CONTINUATION	$537,168
														Subtotal = $537,168

Issue Date FY: 2020 ( Subtotal = $583,477 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	001	5	3/25/2020	COMPETING CONTINUATION	$583,477
2020	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	4	12/3/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $583,477

Issue Date FY: 2018 ( Subtotal = $400,000 )
2018	2018	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	4	7/18/2018	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $400,000

Issue Date FY: 2017 ( Subtotal = $400,000 )
2017	2017	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	3	7/20/2017	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $400,000

Issue Date FY: 2016 ( Subtotal = $400,000 )
2016	2016	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	2	6/20/2016	NON-COMPETING CONTINUATION	$400,000
														Subtotal = $400,000

Issue Date FY: 2015 ( Subtotal = $400,000 )
2015	2015	UNIV OF TEXAS SYS CANCER CTR, M D ANDERSON HOSP/TUM INS	1515 HOLCOMBE BLVD, ROOM 202	HOUSTON	TX	77030	HARRIS	USA	Cardiovascular Diseases Research	000	1	8/31/2015	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $3,794,978

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Controlling the core airway mucin secretion machinery to prevent pathophysiology

Award Number: R01HL129795

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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