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

项目总监/首席研究员（最后、第一、中间）：Kozar RA/ Dong JF 项目概要 创伤是可预防死亡的主要原因，其中大多数死亡是由出血和 由于脉管系统损伤（失血性休克[HS]）引起的相关并发症。当出血结果 越来越多的证据表明，继发性凝血病会导致凝血因子和血小板迅速丧失 由创伤引起的高凝状态发展而来，迅速转变为消耗性凝血病，并且 是由于 HS 引起的低灌注和组织缺血引起的微血管内皮病的一个组成部分。这 内皮病会产生炎症和氧化应激环境，使内皮细胞 (EC) 被激活并且其屏障功能被破坏。这种微血管失调的一个标志是失去 内皮糖萼，通过 syndecan-1 锚定于内皮的碳水化合物保护层。这 糖萼保护内皮细胞免受血液和血浆因子的影响，并具有抗炎、抗血栓、 和抗氧化应激分子。 HS 后，随着 syndecan-1 胞外域的脱落，它会丢失 金属蛋白酶 ADAM-17。糖萼的损失使得内皮具有抗凝血和抗炎作用 具有高度促凝血和促炎作用。关键问题是是什么触发了脱落及其病理性 结果。我们最近的数据表明粘附配体冯维勒布兰德因子 (VWF) 和 外伤继发的内皮病和凝血病以及由此导致的 HS 中的细胞外囊泡 (EV)。在这个 研究中，我们建议检验以下假设：1) syndecan-1 脱落伴随进行性内皮细胞 过度粘附的 VWF 和病理性 EV 释放引起的失调，2) 触发 syndecan-1 脱落 通过在膜脂筏中与 ADAM-17 聚集，以及 3) 将受体结合 A1 结构域暴露在 过度粘附的 VWF 通过将炎症细胞和 EV 束缚到糖萼来增强内皮病 剥离内皮。我们进一步假设糖萼损失之间的协同相互作用， 可以阻断过度粘附的 VWF 和 EV，以预防内皮病。我们建议检验这些假设 通过分析创伤患者的血浆样本和临床信息，确定导致 syndecan-1 脱落和 VWF 体外超粘附活性的结构基础，以及测试新的和 HS 小鼠模型的创新治疗策略旨在实现以下三个目标： 目标 1：确定 进行性微血管失调，最终导致出血性受伤患者的血液衰竭 震惊;目标2：体外研究syndecan-1脱落途径和超粘附VWF的结构， 目标 3：测试新的治疗药物以减轻小鼠创伤引起的微血管失调 HS 型号。我们的提案提出了创新的概念和新颖的机制，提供了新的范式 逆转内皮病和凝血病，为发展奠定基础 作为复苏辅助手段的创新疗法可进一步减少失血性休克相关的发病率 死亡。 OMB 编号 0925-0001/0002（修订版 03/2020 已批准至 02/28/2023） 页面延续格式页面