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Therapeutic targeting of MUC5B in a novel ferret model of idiopathic pulmonary fibrosis

Award Number: U01HL152978
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Therapeutic targeting of MUC5B in a novel ferret model of idiopathic pulmonary fibrosis - Project Summary Idiopathic Pulmonary Fibrosis (IPF) is an incurable, chronic, interstitial lung disease characterized by the accumulation of fibrotic tissue. A major risk factor for developing IPF is a commonly found gain-of-function SNP (rs35705950) in the promoter for the respiratory mucin, MUC5B. However, the mechanistic role of MUC5B in developing IPF remains unknown. Murine animal models have elucidated some fundamental processes of lung fibrosis, but they have failed to recapitulate key features of the human disease and have been unsuccessful in identifying therapies that halt or reverse disease progression, likely because they are poorly suited to replicate the impact of mucus and MUC5B. This highlights the critical need for 1) an animal model that represents the phenotypic and mechanistic features of human IPF, including sustained fibrosis; 2) an improved understanding of molecular mechanisms, including the genetic association with MUC5B overexpression and the connection to disease pathogenesis; and 3) the identification, development and evaluation of novel therapeutic targets based on this knowledge. With a similar lung physiology and cell biology to humans, including Muc5b and other mucus proteins, we have developed a novel bleomycin exposure model using ferrets. Bleomycin exposed ferrets exhibit hallmarks of the human condition including persistent, sustained fibrotic lung disease with collagen-rich fibrosis; Muc5b rich honeycomb cysts; fibroblastic foci; and prominent airway remodeling displaying characteristic ‘proximalization’ of the distal airway spaces. Based on these data, our overarching hypothesis is that heightened Muc5b expression promotes aberrant repair mechanisms to propagate fibrosis, representing a therapeutic target that can be modeled in ferrets. In Aim 1 we will use genetic and pharmacological approaches to test the effects of increased and reduced Muc5b expression on fibrotic lung injury and repair, serving as a validation of model phenotype. In Aim 2 we will determine if smoke exposure (a potent stimulator of Muc5b expression and risk factor for IPF) predisposes ferrets to progressive fibrosis and worsens disease severity. In Aim 3 we will determine if Muc5b is a therapeutic target for pulmonary fibrosis by administering Muc5b-specific antisense oligonucleotides to reduce Muc5b expression or a novel synthetic biopolymer that normalizes Muc5b protein structure and function in pathophysiologic airways. The goal is to develop a model of IPF that provides novel opportunities to define how Muc5b expression contributes to IPF pathogenesis and evaluate Muc5b-directed therapy, providing a definitive advance for IPF research.


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 = $564,741 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	$518,639
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	4	6/24/2024	NON-COMPETING CONTINUATION	$46,102
														Subtotal = $564,741

Issue Date FY: 2023 ( Subtotal = $569,331 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	$569,331
														Subtotal = $569,331

Issue Date FY: 2022 ( Subtotal = $592,858 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$59,286
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	002	2	9/2/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	2	11/18/2021	NON-COMPETING CONTINUATION	$533,572
														Subtotal = $592,858

Issue Date FY: 2021 ( Subtotal = $462,284 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	12/15/2020	NEW	$419,966
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	1	2/12/2021	NEW	$42,318
														Subtotal = $462,284

Grand Total All Awards = $2,189,214

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Therapeutic targeting of MUC5B in a novel ferret model of idiopathic pulmonary fibrosis

Award Number: U01HL152978

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 12/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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