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A Novel PAI-1 Function Drives Lung Fibrosis

Award Number: R01HL163870
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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A Novel PAI-1 Function Drives Lung Fibrosis - Project Summary Progressive scarring of the lung interstitium is a common feature of many systemic and primary lung diseases including Idiopathic Pulmonary Fibrosis (IPF). IPF is a common disorder, and patients diagnosed with this disorder experience substantial morbidity and a median survival of 3-5 years. Although recently approved therapies slow the rate of disease progression, more efficacious interventions that interfere with precise disease mechanisms are desperately needed. Plasminogen activator inhibitor-1 (PAI-1) holds substantial promise as a therapeutic target for lung fibrosis as experiments in multiple complementary animal models reveal a direct correlation between the activity of this molecule and the severity of scarring. These studies substantiate PAI-1 as a critical down-stream mediator of prominent pro-fibrotic stimuli including TGF-β and matrix stiffness. Despite the large amount of data implicating PAI-1 as a critical pro-fibrotic protein, the mechanism by which it promotes fibrosis remains elusive. PAI-1 is a multifunctional protein with inhibitory activity against the plasminogen activators through which it regulates fibrinolysis and wound healing. PAI-1 also interacts with non-protease ligands including the provisional matrix protein vitronectin (VTN). Using mutant proteins lacking specific functions and transgenic mice, we demonstrated that the pro-fibrotic action of PAI-1 is largely independent of its plasminogen activator inhibitory activity and that vitronectin is not required for PAI-1 to fully promote scarring of the lung. These results led us to perform an unbiased proteomic study to identify novel PAI-1 binding partners within the injured lung. With this approach, we identified sortilin related receptor-1 (SorlA) as the most enriched protein. SorlA is a multi-domain receptor implicated in the uptake and intracellular sorting of proteins. Our preliminary data confirm that PAI-1 binds to SorlA and that this interaction is prevented by mutations that suppress the profibrotic activity of PAI-1. We further find that PAI-1 is taken up by key cellular constituents of the fibrotic lesion. Importantly, we also identify a previously unrecognized and potent role for SorlA in lung fibrosis, and using human cells, we find that SorlA expression is upregulated in fibrotic epithelial cells and fibroblasts. These preliminary data motivate our hypothesis that PAI-1 promotes lung fibrosis through an interaction with SorlA that leads to cell uptake, cytosolic localization, and a profibrotic alteration in cell phenotype. To interrogate this hypothesis, we have designed a multifaceted approach incorporating molecular biology techniques, in vitro experiments with cells from patients and mice (as well as cell lines), and in vivo experiments using transgenic mice, mutant PAI-1 proteins, and complementary models of lung fibrosis. To accomplish our proposed studies, we have brought together a synergistic investigative team with expertise in PAI-1, epithelial cell and fibroblast biology, and animal modeling, and the results from our studies promise to elucidate previously unexplored mechanisms and novel therapeutic targets.


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: 2026 ( Subtotal = $671,209 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	4	2/11/2026	NON-COMPETING CONTINUATION	$671,209
														Subtotal = $671,209

Issue Date FY: 2025 ( Subtotal = $706,535 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	001	3	8/18/2025	NON-COMPETING CONTINUATION	$70,654
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	3	11/15/2024	NON-COMPETING CONTINUATION	$635,881
														Subtotal = $706,535

Issue Date FY: 2024 ( Subtotal = $695,226 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	2	11/13/2023	NON-COMPETING CONTINUATION	$638,472
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	001	2	6/26/2024	NON-COMPETING CONTINUATION	$56,754
														Subtotal = $695,226

Issue Date FY: 2023 ( Subtotal = $696,684 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	1	12/12/2022	NEW	$696,684
														Subtotal = $696,684

Grand Total All Awards = $2,769,654

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A Novel PAI-1 Function Drives Lung Fibrosis

Award Number: R01HL163870

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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