Trauma and Shock-Induced Microvascular Dysregulation and Coagulopathy

创伤和休克引起的微血管失调和凝血病

• 批准号: 10579187
• 负责人: Jing-Fei Dong
• 金额: $ 60.08万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579187
• 关键词: ADAMTS; Acute; Adhesives; Anti-Inflammatory Agents; Antibodies; Anticoagulants; Binding; Blood; Blood Cells; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Carbohydrates; Cause of Death; Cells; Cessation of life; Clinical; Complex; Cysteine; Data; Development; Endothelial Cells; Endothelium; Environment; Exposure to; Failure; Fluorescence Resonance Energy Transfer; Foundations; Functional disorder; Glycocalyx; Hemorrhage; Hemorrhagic Shock; Hemostatic Agents; In Vitro; Inflammatory; Injury; Ischemia; Lead; Leukocytes; Ligands; Measures; Mediating; Membrane Lipids; Membrane Microdomains; Metalloproteases; Microscopy; Modality; Molecular Conformation; Morbidity - disease rate; Mus; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathologic; Pathway interactions; Patients; Plasma; Principal Investigator; Proteins; Proteomics; Publishing; Recombinants; Research; Resuscitation; Risk Assessment; Role; Rosemary; Sampling; Secondary to; Severities; Shock; Site; Structure; Sucrose; Surface; System; TNF-alpha converting enzyme; Techniques; Testing; Therapeutic; Therapeutic Agents; Thrombophilia; Time; Tissues; Trauma; Trauma patient; Traumatic Brain Injury; Ultracentrifugation; disability; enhancing factor; experimental study; extracellular vesicles; hemodynamics; hypoperfusion; improved outcome; in vitro activity; injured; innovation; insight; mortality; mouse model; novel; novel therapeutics; oxidation; prevent; preventable death; programs; receptor binding; response; severe injury; syndecan; thrombotic; vascular injury; von Willebrand Factor

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

项目主任/首席研究员（后、一、中）：Kozar RA/ Dong JF