Tuesday, July 1, 2025 7/1/2025

Activation of matrix metalloproteinase-9 is essential to overcome failed fibrosis resolution

Award Number: R01HL173030
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Activation of matrix metalloproteinase-9 is essential to overcome failed fibrosis resolution - PROJECT SUMMARY A key feature of interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF), is the excessive deposition of extracellular matrix (ECM) and scar tissue. Fibroblasts persist in fibrotic lungs and lay down matrix, contributing to a progressive and persistent phenotype in patients. Matrix metalloproteinases (MMPs) are enzymes that cleave and break down ECM during wound repair and the degradation and removal of scar tissue is essential for fibrosis resolution. The expression of MMP-9 is increased in the lungs of IPF patients. However, MMP-9 is not present in the active form rendering it unable to cleave collagens. Our preliminary data in MMP-9 deficient mice support that active MMP-9 is necessary for fibrosis resolution. We therefore asked if MMP-9 activation is inhibited in IPF lungs limiting its ability to successfully initiate repair through matrix degradation. MMP-9 is activated from its latent-form through a series of activating enzymes beginning with urokinase plasminogen activating enzyme (uPA). uPA cleaves plasminogen into plasmin which in turn is a major activator of MMP-9. However, in IPF, plasminogen activator inhibitor-1 (PAI-1) inhibits uPA thus inhibiting the activation cascade needed for downstream MMP-9-activation and matrix degradation. Due to the poor quality and significantly reduced life expectancy associated with ILDs, it is becoming increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the central hypothesis that MMP-9 activation by plasmin is necessary for fibrosis resolution and that this pathway can be induced through beneficial TNF-a signaling. Based on our robust preliminary studies, we propose three specific aims to test this central hypothesis. Specific Aim 1 will test the hypothesis that beneficial TNF-a signaling increases urokinase and expression of MMP-9 in fibroblasts. This will be tested using genetic approaches to determine if conditional deletion of MMP-9 in fibroblasts is sufficient to prevent fibrosis resolution in a spontaneously resolving fibrosis model and if exogenous TNF-a is sufficient to activate the uPA/plasminogen/MMP-9 pathway, inducing resolution in a non-resolving fibrosis model. Specific Aim 2 will test the hypothesis that MMP-9 activation by plasmin contributes to the resolution of bleomycin-induced fibrosis. This will be tested through the generation of a non-cleavable MMP-9 mutant and through pharmacological inhibition of MMP-9 in vivo. Specific Aim 3 will test the hypothesis that a clinical formulation of recombinant urokinase (KinlyticTM) promotes the resolution of established pulmonary fibrosis by activating pro-MMP-9 through the plasminogen/plasmin cascade. This will be tested by treating mice with persistent fibrosis with recombinant urokinase to induce plasmin and MMP-9 activation as a mechanism of fibrosis resolution. The proposed studies will provide a novel understanding about how activating an anti-fibrotic pathway (uPA/plasminogen/MMP-9) may contribute to the resolution of fibrosis. Furthermore, the outcomes of these pre-clinical, therapeutic studies will significantly impact our understanding of the mechanisms that control fibrosis resolution.


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 = $678,756 )
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	001	2	6/26/2025	NON-COMPETING CONTINUATION	$67,876
2025	2025	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	2	4/15/2025	NON-COMPETING CONTINUATION	$610,880
														Subtotal = $678,756

Issue Date FY: 2024 ( Subtotal = $678,756 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	001	1	6/18/2024	NEW	$67,876
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	1	3/4/2024	NEW	$610,880
														Subtotal = $678,756

Grand Total All Awards = $1,357,512

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Activation of matrix metalloproteinase-9 is essential to overcome failed fibrosis resolution

Award Number: R01HL173030

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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