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The Transmembrane Protein Disulfide Isomerase TMX1 Negatively Regulates Thrombosis

Award Number: R01HL162845
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The Transmembrane Protein Disulfide Isomerase TMX1 Negatively Regulates Thrombosis - The control of platelet function and coagulation is a fine balance between activation and inhibitory mechanisms. Platelets become rapidly activated by multiple receptors agonists and have a central role in thrombosis in acute coronary syndromes, and other disease states. Similarly, naturally occurring anticoagulants are critical in preventing fibrin generation and thrombosis. Fivemembers of theprotein disulfide isomerase (PDI) family of enzymes, PDI, ERp57, ERp5, ERp72 and ERp46 potentiate activation of IIb3 and thrombosis.We discovered atransmembrane member of the PDI family found to inhibit activation of IIb3 and member of the PDI family in platelets, TMX1, which thrombosis. TMX1 is the first acts by a novel mechanism of oxidizing thiols to disulfide bonds and is the last checkpoint inhibitor of the platelet activation pathways that lead to conformational changes in IIb3 and fibrinogen binding. The prothrombotic PDIs are secreted from platelets and endothelial cells and support fibrin generation at the site of vascular injury. We found that TMX1 is expressed on platelets and endothelial cells but, negatively procoagulant in contras to the other PDIs, TMX1 regulates fibrin generation. One mechanism by which TMX1 inhibits coagulation is by limiting the effect of endothelial cells and platelets. We propose to study t vascular TMX1 as a dual negative regulator of platelets and coagulation by addressing the following Specific Aims. We will characterize 1. the role of TMX1 in thrombus formation; 2. the mechanism of inhibition of IIb3 activation by TMX1; 3. the effect of TMX1 on the other platelet PDIs, and on other platelet surface substrates. A principal technique used will be the laser-induced injury model of thrombosis. We will study the mechanism by which TMX1 negatively regulates coagulation. To determine the underlying mechanisms by which TMX1 inhibits platelet function we will integrate a platelet knockout mouse model with mass spectrometry-based identification of functional cysteines. This proposal will determine the mechanisms by which TMX1 works, and how TMX1 counterbalances the PDI enzymes that support activation of IIb3. Characterization of the negative regulatory role of TMX1 will provide novel insight into how the network of PDI enzymes regulate thrombosis. Studies on how TMX1 maintains the balance between thrombosis and hemostasis will elucidate optimal ways to promote hemostasis and inhibit thrombosis and provide a basis for studying TMX1 in disease states.


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 = $655,760 )
2026	2026	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	4	2/11/2026	NON-COMPETING CONTINUATION	$655,760
														Subtotal = $655,760

Issue Date FY: 2025 ( Subtotal = $690,273 )
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	3	12/17/2024	NON-COMPETING CONTINUATION	$621,245
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	3	8/15/2025	NON-COMPETING CONTINUATION	$69,028
														Subtotal = $690,273

Issue Date FY: 2024 ( Subtotal = $681,384 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	2	1/15/2024	NON-COMPETING CONTINUATION	$625,761
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$55,623
														Subtotal = $681,384

Issue Date FY: 2023 ( Subtotal = $714,505 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	1	1/13/2023	NEW	$714,505
														Subtotal = $714,505

Grand Total All Awards = $2,741,922

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The Transmembrane Protein Disulfide Isomerase TMX1 Negatively Regulates Thrombosis

Award Number: R01HL162845

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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