Tuesday, September 16, 2025 9/16/2025

Inhibiting biomechanical platelet aggregation to prevent arterial thrombosis without compromising hemostasis

Award Number: R00HL153678
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Inhibiting biomechanical platelet aggregation to prevent arterial thrombosis without compromising hemostasis - Project Summary/Abstract Arterial thrombosis, which describes the formation of abnormal blood clots in the artery, is a highly fatal disease that claims ~500,000 American lives per year. A symbolic feature of arterial thrombosis is the elevated shear rate and shear force generated by stenosis, which facilitates platelet aggregation towards vessel occlusion. Unfortunately, current therapeutic strategies are ineffective in inhibiting the prothrombotic effects of the pathological blood flow, and have a major risk of excessive bleeding. The overall objective of this proposal is to establish a mechanism-driven strategy to better treat arterial thrombosis. Our lab's previous works and my research identified that the prothrombotic effects of pathological blood flow result from a phenomenon called “biomechanical platelet aggregation”, in which mechanical force drives platelets to crosslink. Von Willebrand factor (VWF) is a plasma protein that mediates platelet crosslinking by binding to platelet receptor GPIbα. In my preliminary study, I worked on an artificially designed triple-residue VWF mutation named `M13', which inhibited VWF in mediating biomechanical platelet aggregation and shear-induced thrombogenesis, but did not affect platelet adhesion or hemostasis. Based on these findings, I hypothesize that: biomechanical platelet aggregation is a key factor to arterial thrombosis, and its inhibition can suppress arterial thrombosis without compromising hemostasis. I propose 4 aims to step-by-step establish anti-thrombotic approaches targeting the biomechanical platelet aggregation. Aim 1 will combine biomechanics and hematology assays to study the mechanism underlying M13's function in inhibiting biomechanical platelet aggregation but not adhesion. Aim 2 will establish a microfluidic-based assay that concurrently assesses platelet adhesion and shear-induced thrombogenesis, which allows the screening of anti-thrombotics targeting biomechanical platelet aggregation. In Aim 3, a monoclonal antibody against VWF, NMC4, was identified to be functionally aligned with my anti-thrombotic strategy. I will collaborate with my postdoctoral lab and use NMC4 as a prototype to design and produce anti-thrombotic agents. A 3-step screening procedure will be established to select candidate agents with the best functional performance. Lastly in Aim 4, I will expand my anti-thrombotic strategy to another platelet receptor also important to biomechanical platelet aggregation: integrin αIIbβ3. I will explore the efficacy and safety of inhibiting both VWF- and αIIbβ3-mediated biomechanical platelet aggregation in treating arterial thrombosis exacerbated by diabetes. Overall, this research will be accomplished in the setting of a comprehensive career development program designed to help me achieve my career goal as an independent researcher in the interdisciplinary field of vascular biology, mechanobiology and bioengineering. During the K99 phase, I will continue to gain expertise in biochemical, preclinical and translational approaches. My mentor, collaborators and consultants will together guide me in the steps towards successful transition to independence over the course of the award period.


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: 2025 ( Subtotal = -$77,350 )
2025	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	000	5	8/5/2025	NON-COMPETING CONTINUATION	-$77,350
														Subtotal = -$77,350

Issue Date FY: 2024 ( Subtotal = $248,792 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	000	5	5/10/2024	NON-COMPETING CONTINUATION	$223,914
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	001	5	6/21/2024	NON-COMPETING CONTINUATION	$24,878
														Subtotal = $248,792

Issue Date FY: 2023 ( Subtotal = $248,792 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	000	4	4/6/2023	NON-COMPETING CONTINUATION	$248,792
														Subtotal = $248,792

Issue Date FY: 2022 ( Subtotal = $329,415 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	001	3	7/8/2022	EXTENSION WITH OR WITHOUT FUNDS	$80,560
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Blood Diseases and Resources Research	000	3	3/29/2022	EXTENSION WITH OR WITHOUT FUNDS	$248,855
														Subtotal = $329,415

Grand Total All Awards = $749,649

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Inhibiting biomechanical platelet aggregation to prevent arterial thrombosis without compromising hemostasis

Award Number: R00HL153678

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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