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Role of disrupted ASL pH regulation in small airways in CF lung disease pathogenesis

Award Number: R01HL153165
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Role of disrupted ASL pH regulation in small airways in CF lung disease pathogenesis - PROJECT SUMMARY / ABSTRACT Cystic fibrosis (CF) is a common genetic disease caused by a defect in the CF transmembrane conductance regulator (CFTR). The pathogenesis of CF lung disease is unclear and controversial, at least partially due to lack of studies in an appropriate CF animal model. In addition, most studies regarding the pathogenesis rely on data from cultured human diseased large proximal airways, such as tracheal and bronchial tissue. However, pathological and clinical data suggest that the disease is initiated in small airways with a diameter <2mm. Iowa group has engineered pigs with deletion or mutation of CFTR. These pigs mimic human CF, including development of spontaneous infections and obstruction of airways with mucus and inflammatory cells. This model provides an unprecedented opportunity to investigate the pathogenesis of CF lung disease. Our objective for this study is to investigate how loss of CFTR leads to host defense defects in CF small airway epithelia and if viral vector mediated delivery of CFTR cDNA to CF small airways will rescue host defense defects. Our overall hypothesis is that AAV4 mediated delivery of CFTR will correct ASL properties and restore host defense function of small airway epithelium in CF. In Aim 1, we will use AAV4 to deliver CFTR cDNA in cultured small airway epithelial cells from CF pigs and examine ASL properties including pH and viscosity and bacterial killing abilities. In Aim 2, we will use human small airway epithelia from CF patients to test the hypothesis. In Aim 3, we will examine the cellular tropism and efficiency of AAV4 mediated gene delivery to small airway epithelium in live pigs and human lung explant. The proposed studies will lead to a better understanding of the CFTR-mediated host defense mechanisms and illustrate a potentially important yet previously underappreciated role of small airway epithelial cells in pathogenesis of CF lung disease.


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 = $589,634 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Lung Diseases Research	001	4	7/18/2024	SUPPLEMENT FOR EXPANSION	$75,027
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Lung Diseases Research	000	4	7/11/2024	NON-COMPETING CONTINUATION	$514,607
														Subtotal = $589,634

Issue Date FY: 2023 ( Subtotal = $525,109 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Lung Diseases Research	000	3	6/27/2023	NON-COMPETING CONTINUATION	$525,109
														Subtotal = $525,109

Issue Date FY: 2022 ( Subtotal = $525,109 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Lung Diseases Research	000	2	7/20/2022	NON-COMPETING CONTINUATION	$525,109
														Subtotal = $525,109

Issue Date FY: 2021 ( Subtotal = $553,359 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Lung Diseases Research	000	1	8/4/2021	NEW	$553,359
														Subtotal = $553,359

Grand Total All Awards = $2,193,211

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Role of disrupted ASL pH regulation in small airways in CF lung disease pathogenesis

Award Number: R01HL153165

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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