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

Award Number: R00HL166778
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Lipid peroxidation- and pyroptosis-induced tissue factor activation in pathogen-induced blood coagulation - 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 viral infections, but its role in TF activation is unknown. Our preliminary studies demonstrate that ORF3A, an accessory viral protein induce TF activation in a phosphatidylserine (PS)-dependent mechanism that requires TMEM16F, similar to PS-dependent TF activation in pyroptosis. In Aim 1, my lab will investigate the underlying mechanisms that govern ORF3a-induced TF activation emphasizing the key roles of programmed-cell death. 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, my lab will use chemical and genetic approaches to investigate whether HNE-induced TF activation and intravascular coagulation activation is mediated through programmed cell death. 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, my lab 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 = $249,000 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Blood Diseases and Resources Research	000	3	6/3/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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

Award Number: R00HL166778

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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