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Lipid peroxidation- and pyroptosis-induced tissue factor activation in pathogen-induced blood coagulation

Award Number: K99HL166778
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Lipid peroxidation- and pyroptosis-induced tissue factor activation in pathogen-induced blood coagulation - Project Summary/Abstract Tissue factor (TF), the primary initiator of the blood coagulation cascade, is carefully regulated to prevent aberrant coagulation activation. However, pathological conditions including bacterial and viral infection induce intravascular TF expression and lead to thrombosis. As TF-induced thrombosis is a major cause of acute myocardial infarction, ischemic stroke, and pulmonary embolism, improved understanding of the mechanisms of pathological TF activation may lead to new therapeutic targets. Pyroptosis, a form of inflammatory cell death, drives TF-mediated intravascular coagulation activation in bacterial sepsis. Emerging studies also implicate inflammasome activation in SARS-CoV-2 infection, but its role in TF activation is unknown. Our preliminary studies demonstrate that SARS-CoV-2 and specifically its accessory protein ORF3A induce TF activation in a phosphatidylserine (PS)-dependent mechanism that requires TMEM16F, similar to PS-dependent TF activation in pyroptosis. In Aim 1, we will investigate whether ORF3a-induced TF activation is driven by inflammasome- mediated pyroptosis. Lipid peroxidation and its highly reactive end products such as 4-hydroxy-2-nonenal (HNE) are involved in various forms of programmed cell death including pyroptosis. However, the role of HNE, the most stable and toxic reactive aldehyde produced during lipid peroxidation, in pyroptosis-associated TF and coagulation activation is not known. Our preliminary data showed that HNE induces PS-dependent TF activation in LPS-primed macrophages and causes intravascular coagulation activation in mice. However, the complete mechanism by which HNE induces PS externalization and TF activation is not known. In Aim 2, we will use chemical genetic approaches to dissect the mechanism of HNE-induced TF activation via pyroptosis in vitro and in vivo. Although lipid peroxidation plays a central role in cell death and coagulation activation in bacterial sepsis, a therapeutically targetable enzyme responsible for the unbridled lipid peroxidation and generation of pathological levels of reactive radicals such as HNE is not known. In Aim 3, we will use genetically modified mice deficient in lipid peroxidation and HNE formation to investigate TF-dependent pathologic coagulation activation and thrombosis during sepsis. A successful completion of these studies will help delineate a common pathway involved in pathologic TF activation across varied pathogenic infections and will also help identify a specific therapeutically targetable enzyme to attenuate TF activation in disease.


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 = $0 )
2026	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	5/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	1/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $164,484 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	4/16/2024	NON-COMPETING CONTINUATION	$164,484
														Subtotal = $164,484

Issue Date FY: 2023 ( Subtotal = $164,484 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	3/24/2023	NEW	$164,484
														Subtotal = $164,484

Grand Total All Awards = $328,968

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Lipid peroxidation- and pyroptosis-induced tissue factor activation in pathogen-induced blood coagulation

Award Number: K99HL166778

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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