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Role of circulating Osteopontin and of Innate Immune Cell CD44 in Tissue Injury-induced Remote Lung Inflammation

Award Number: R01HL177000
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Role of circulating Osteopontin and of Innate Immune Cell CD44 in Tissue Injury-induced Remote Lung Inflammation - PROJECT SUMMARY ABSTRACT The overall goal of our research is to develop novel strategies to prevent or treat secondary organ complications in multiorgan failure. Acute kidney injury frequently negatively impacts oxygenation in multiorgan failure, causing very high mortality due to a lack of therapies. Molecular mechanisms and mediators of this detrimental kidney- lung crosstalk are incompletely understood. We recently identified circulating osteopontin (OPN, Spp1) released by the injured kidney after acute kidney injury as a novel key mediator of remote lung inflammation with respiratory failure. Consistent with this, elevated OPN serum levels correlate with increased mortality and need for ventilation in multiorgan failure patients. OPN can interact with integrins and CD44 receptors and possibly through its two thrombin cleavage fragments. It is unknown which OPN receptor interactions are required for remote lung inflammation, which cells OPN targets, and which signals downstream of OPN attract neutrophils to lung capillaries. Our central hypotheses is that OPN or its thrombin-cleaved fragments bind to its receptor(s) integrin and/or CD44 on innate lung immune cells that in turn produce signals that attract neutrophils to lung capillaries. Our preliminary work provides evidence for a role of OPN in CD44+ innate lung immune cells in remote lung inflammation and for signals they produce that attract neutrophils. The rationale for this project is that completion will for the first time (1) identify lung target cells and receptors of remote lung inflammation, (2) define OPN domains involved in remote lung inflammation, and (3) directly visualize initiation of remote lung inflammation and the effect of blockade of predicted innate immune cell-derived neutrophil chemoattractant signals in vivo. We plan to test our central hypotheses with three specific aims: Aim 1: Determine which OPN domains are required to induce remote lung inflammation and whether OPN thrombin cleavage is required. We will test (1) whether OPN or OPN mutants reverse protection of AKI-injured OPN-KO mice when injected or (2) induce signaling and production of cytokines in monocyte or macrophage cell lines. We will also test knock-in mice with a mutation that renders OPN uncleavable by thrombin. Aim 2: Determine whether CD44 in lung innate immune cells is required for remote lung inflammation. We will (1) test cell-type specific knockout of CD44 in innate immune cells or transplantation approaches in remote lung inflammation and (2) test for OPN:CD44 interaction and CD44’s requirement for OPN action in remote lung inflammation. Aim 3: Test innate immune cell- derived signals predicted to recruit neutrophils in remote lung inflammation. Using intravital two-photon imaging, we will directly visualize initiating steps of remote lung inflammation after AKI and test the effect of blocking predicted neutrophil attractant signals. This contribution is significant because it is expected to have translational impact in the development of treatments for detrimental kidney-lung crosstalk in multiorgan failure, complications with high mortality. Our research is innovative, in our opinion, because it would identify critical mediators, target cells types, and mechanisms in remote lung inflammation, and provide guidance for translation into patients.


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 = $559,802 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Lung Diseases Research	000	2	2/13/2026	NON-COMPETING CONTINUATION	$542,664
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Lung Diseases Research	001	2	3/13/2026	NON-COMPETING CONTINUATION	$17,138
														Subtotal = $559,802

Issue Date FY: 2025 ( Subtotal = $583,233 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Lung Diseases Research	000	1	3/25/2025	NEW	$583,233
														Subtotal = $583,233

Grand Total All Awards = $1,143,035

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Role of circulating Osteopontin and of Innate Immune Cell CD44 in Tissue Injury-induced Remote Lung Inflammation

Award Number: R01HL177000

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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