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Characterizing a novel pathway involving Plasminogen activator-inhibitor 1 and Sortilin-related receptor 1 as a key driver in pulmonary fibrosis

Award Number: F31HL184568
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Characterizing a novel pathway involving Plasminogen activator-inhibitor 1 and Sortilin-related receptor 1 as a key driver in pulmonary fibrosis - Project Summary Idiopathic pulmonary fibrosis (IPF) is a form interstitial lung disease of unknown etiology. It is the most common chronic fibrosing lung disease with a median survival of 3-5 years after diagnosis. Fibrosis is thought to be a form of pathologic wound healing that is characterized by excessive accumulation of the extracellular matrix leading to the formation of scar tissue. Fibrotic progression in IPF results in lung dysfunction and ultimately death due to respiratory failure or other severe complications. Given its rising prevalence, lethality, and lack of curative treatments, there is an urgent need to elucidate the molecular mechanisms underlying IPF pathophysiology. Plasminogen activator-inhibitor 1 (PAI-1), has been widely implicated in the pathology of pulmonary fibrosis. PAI- 1 is a critical regulator of fibrinolysis and wound healing through its inhibitory action against tissue and urokinase type plasminogen activators (tPA/uPA). It is also known the interact with the provisional matrix protein, vitronectin, which stabilizes its active confirmation. However, we and others found that PAI-1 does not promote fibrosis through either of these known interactions. Using a proteomics approach, we have identified the intracellular sorting receptor, Sortilin-related receptor 1 (SorLA), as the most highly enriched binding partner for PAI-1 in the fibrosing lung, and our preliminary data reveal that PAI-1 requires SorLA to exert its full profibrotic effects. Additionally, we found that both PAI-1 and SorLA expression are upregulated in human IPF lung tissue, and that they colocalize in cells. Moreover, cellular uptake of PAI-1 is increased in cells expressing SorLA compared to cells not expressing SorLA. Based on these data, we hypothesize that PAI-1 promotes pulmonary fibrosis through unknown cytosolic interactions mediated by SorLA. We will test this hypothesis with two independent, but complementary aims. Aim 1 will map the intracellular trafficking patterns of PAI-1 and SorLA and determine their effects in promoting fibrotic cell phenotypes. Aim 2 will use proximity labeling and proteomic analysis to identify previously unknown PAI-1 cytosolic interactions and investigate their impact on profibrotic signaling and cell phenotypes. The proposed studies will characterize novel mechanisms that will be informative for the development of IPF treatments. The studies planned to address these two aims will provide me with significant training opportunities, including in the isolation, culture and characterization of primary cells from transgenic mice, experience with proximity labeling, and proteomics. I will also gain experience in bioinformatic analysis techniques. These skills will be directly developed in pursuit of the specific experiments proposed in my research plan and will serve as a solid foundation for my long-term goal of becoming an independent investigator. The environment at the University of Michigan and in the Department of Molecular and Integrative Physiology is ideally suited to support my studies and lay the foundation for my future success.


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 = $39,031 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	001	1	4/17/2026	NEW	$0
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Lung Diseases Research	000	1	4/17/2026	NEW	$39,031
														Subtotal = $39,031

Grand Total All Awards = $39,031

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Characterizing a novel pathway involving Plasminogen activator-inhibitor 1 and Sortilin-related receptor 1 as a key driver in pulmonary fibrosis

Award Number: F31HL184568

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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