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Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy

Award Number: R01GM140983
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy - Program Director/Principal Investigator (Last, First, Middle): Kozar RA/ Dong JF Project Summary Trauma is the leading cause of preventable death, with the majority of deaths caused by hemorrhage and associated complications due to injury to the vasculature (hemorrhagic shock [HS]). While hemorrhage results in the rapid loss of coagulation factors and platelets, increasing evidence suggests that secondary coagulopathy develops from a trauma-induced hypercoagulable state that rapidly turns into consumptive coagulopathy, and is an integral part of microvascular endotheliopathy due to HS-induced hypoperfuson and tissue ischemia. The endotheliopathy creates an inflammatory and oxidative stress environment where endothelial cells (ECs) are activated and their barrier function disrupted. A hallmark of this microvascular dysregulation is loss of the endothelial glycocalyx, a protective layer of carbohydrates anchored to the endothelium by syndecan-1. The glycocalyx shields endothelial cells from blood and plasma factors and hosts anti-inflammatory, anti-thrombotic, and anti-oxidative stress molecules. It is lost following HS with shedding of the syndecan-1 ectodomain by the metalloprotease ADAM-17. Loss the of glycocalyx makes the anti-coagulant and anti-inflammatory endothelium highly procoagulant and proinflammatory. The critical question is what triggers shedding and its pathological consequences. Our recent data suggests causal roles of the adhesive ligand von Willebrand factor (VWF) and extracellular vesicles (EVs) in endotheliopathy and coagulopathy secondary to trauma and resultant HS. In this study, we propose to test the hypotheses that: 1) syndecan-1 shedding with progressive endothelial dysregulation caused by release of hyperadhesive VWF and pathologic EVs, 2) syndecan-1 shedding is triggered by clustering with ADAM-17 in membrane lipid rafts, and 3) exposure of the receptor-binding A1 domain on hyperadhesive VWF enhances endotheliopathy by tethering inflammatory cells and EVs to the glycocalyx- stripped endothelium. We further hypothesize that the synergistic interplay between glycocalyx loss, hyperadhesive VWF, and EVs can be blocked to prevent endotheliopathy. We propose to test these hypotheses by analyzing plasma samples and clinical information from trauma patients, defining pathways leading to syndecan-1 shedding and the structural basis of VWF hyperadhesive activity in-vitro, and testing new and innovative therapeutic strategies in mouse models of HS in the following three aims: Aim 1: To determine the progressive microvascular dysregulation culminating in blood failure of injured patients with hemorrhagic shock; Aim 2: To study the pathway of syndecan-1 shedding and the structure of hyperadhesive VWF in-vitro, and Aim 3: To test new therapeutic agents to mitigate trauma-induced microvascular dysregulation in mouse models of HS. Our proposal puts forth innovative concepts and novel mechanisms that offer a new paradigm for the reversal of endotheliopathy and coagulopathy that can establish the foundation for the development of innovative therapeutics as resuscitation adjuncts to further reduce hemorrhagic shock-related morbidity and mortality. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page


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 MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	11/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $603,917 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	4	1/16/2025	NON-COMPETING CONTINUATION	$543,525
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	4	8/20/2025	NON-COMPETING CONTINUATION	$60,392
														Subtotal = $603,917

Issue Date FY: 2024 ( Subtotal = $615,259 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	3	6/12/2024	NON-COMPETING CONTINUATION	$61,526
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	1/22/2024	NON-COMPETING CONTINUATION	$553,733
														Subtotal = $615,259

Issue Date FY: 2023 ( Subtotal = $600,821 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	2	2/15/2023	NON-COMPETING CONTINUATION	$60,082
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	1/18/2023	NON-COMPETING CONTINUATION	$540,739
														Subtotal = $600,821

Issue Date FY: 2022 ( Subtotal = $614,446 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	2/24/2022	NEW	$614,446
														Subtotal = $614,446

Grand Total All Awards = $2,434,443

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Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy

Award Number: R01GM140983

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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