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Platelet Metabolic Stress Induces Thrombo-Inflammation to Drive Endothelial Dysfunction in PH

Award Number: R01HL166985
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Platelet Metabolic Stress Induces Thrombo-Inflammation to Drive Endothelial Dysfunction in PH - Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure, that leads to vascular remodeling and right heart failure. While endothelial cell (EC) dysfunction drives vascular remodeling, the events that instigate EC injury are unclear. Platelets circulate proximal to ECs and experimental platelet depletion has been shown to attenuate pathogenesis in PAH models. However, the mechanisms responsible for this effect remain elusive. Notably, platelets are highly metabolically active and mediate vascular inflammation, but these functions have not been fully considered in PAH. We showed that platelets from PAH patients display metabolic dysfunction with increased fatty acid oxidation (FAO) and mitochondrial oxidants (mtROS). Preliminary data indicate this dysfunction is caused by upregulation of the mitochondrial GTPase and mitofusin-1 (MFN-1), stimulating activation of the NLRP3-dependent inflammasome. Cleavage of caspase-1, an essential component of the inflammasome, leads to secretion of interleukin-1β (IL-1 β), platelet degranulation, and surface expression of p-selectin (collectively labeled thrombo-inflammation). New data demonstrate that these platelet-dependent events trigger EC oxidant production (via NADPH oxidase-1; NOX1) and EC proliferation. Hypothesis: Platelet MFN1-dependent mitochondrial dysfunction triggers inflammasome mediated thrombo-inflammation, which leads to EC dysfunction in PAH. Aim 1: Determine how MFN1-dependent platelet mitochondrial dysfunction triggers inflammasome activation. Using biochemical measures in PAH patients’ platelets, we will link mitochondrial dysfunction to inflammasome activation. We will induce PAH in transgenic murine models of platelet-specific MFN1 and caspase-1 silencing, supplemented with lipidomics and redox modulation, to determine the mechanism by which FAO and mtROS triggers inflammasome activation. PAH will be induced in a novel secretome mouse to define vasoactive molecules released by platelet degranulation in PAH. Aim 2: Determine the mechanism(s) by which platelet-driven thrombo-inflammatory signaling causes EC dysfunction in PAH. Using human/murine platelet-EC co-cultures, we will characterize platelet-driven EC NOX1 activation and proliferation. Using antagonists to signaling mediated by IL-1β and platelet granule factors identified in Aim 1, we will determine the platelet-dependent signaling axis that causes EC dysfunction. The contribution of p-selectin dependent platelet-neutrophil aggregates will also be tested. We will utilize EC-specific NOX1 knockout mice to test the role of platelet-mediated NOX1 activation in PAH. Aim 3: Determine if VX-765, which inhibits caspase-1 to block inflammasome activation, and attenuates PAH pathogenesis. We will test the efficacy of VX-765 (in clinical trials for non-PAH pathologies) in rodent models of PAH. These studies will uncover a novel intra-platelet to EC signaling axis that defines the role of platelets in PAH pathogenesis and reveals potential 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 = $706,994 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	7/15/2026	NON-COMPETING CONTINUATION	$706,994
														Subtotal = $706,994

Issue Date FY: 2025 ( Subtotal = $721,423 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	3	7/23/2025	NON-COMPETING CONTINUATION	$721,423
														Subtotal = $721,423

Issue Date FY: 2024 ( Subtotal = $706,994 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	2	8/19/2024	NON-COMPETING CONTINUATION	$706,994
														Subtotal = $706,994

Issue Date FY: 2023 ( Subtotal = $721,423 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	1	7/31/2023	NEW	$721,423
														Subtotal = $721,423

Grand Total All Awards = $2,856,834

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Platelet Metabolic Stress Induces Thrombo-Inflammation to Drive Endothelial Dysfunction in PH

Award Number: R01HL166985

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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