Thursday, January 1, 2026 1/1/2026

Biased PAR1 Agonism in Sickle Cell Disease

Award Number: R01HL155193
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/10/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Biased PAR1 Agonism in Sickle Cell Disease - PROJECT SUMMARY Title: Biased PAR1 Agonism in Sickle Cell Disease Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene, resulting in altered red cell physiology that drives chronic hemolytic anemia and painful vaso-occlusive crisis (VOC) triggered by microvascular occlusion/stasis. VOC is the leading cause of hospitalizations of sickle cell patients. Activation of the main thrombin receptor, protease activated receptor 1 (PAR1), enhances the interactions between endothelial cells and sickle RBCs. In my recently published study, I demonstrated that PAR1 deficiency on nonhematopoietic cells or inhibition of PAR1 with vorapaxar attenuates microvascular stasis in a mouse model of SCD. In addition to thrombin, PAR1 is also activated by activated protein C (APC). The APC-mediated activation of PAR1 is referred to as “biased agonism” because it activates a different signaling pathway than thrombin and ultimately induces cytoprotective and anti-inflammatory effects. My central hypothesis is that canonical thrombin/PAR1 signaling contributes to microvascular stasis whereas non-canonical APC/PAR1 signaling reduces microvascular stasis and thromboinflammation. I hypothesize that inducing beneficial PAR1 biased signaling will be advantageous compared to complete PAR1 inhibition, which blocks the deleterious thrombin- dependent signaling as well as beneficial APC signaling. In the first aim I will compare the roles of thrombin/PAR1 and APC/PAR1 signaling on coagulation, inflammation, and microvascular stasis in sickle cell mice using mice with PAR1 point mutations that select for activation by either thrombin or APC. In the second aim, I will compare the therapeutic potential of a signaling-selective form of APC, 3K3A-APC, to two inhibitors of PAR1, parmodulin 2 and vorapaxar, on inflammation, microvascular stasis, and acute chest syndrome. Finally, in the third aim, I will investigate the effects of biased PAR1 agonism on mortality and end-organ damage in sickle mice. These studies will investigate the role of biased PAR1 signaling in the pathology of SCD.


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	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	5	11/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $388,750 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	5	12/11/2024	NON-COMPETING CONTINUATION	$388,750
														Subtotal = $388,750

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	4	6/14/2024	NON-COMPETING CONTINUATION	$38,875
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	4	1/10/2024	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $388,750 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	3	1/16/2023	NON-COMPETING CONTINUATION	$349,875
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	3	3/10/2023	NON-COMPETING CONTINUATION	$38,875
														Subtotal = $388,750

Issue Date FY: 2022 ( Subtotal = $388,750 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$38,875
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	2	12/27/2021	NON-COMPETING CONTINUATION	$349,875
														Subtotal = $388,750

Issue Date FY: 2021 ( Subtotal = $388,750 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	1	1/9/2021	NEW	$349,875
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	1	6/14/2021	NEW	$38,875
														Subtotal = $388,750

Grand Total All Awards = $1,943,750

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Biased PAR1 Agonism in Sickle Cell Disease

Award Number: R01HL155193

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/10/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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