Endothelial Glycocalyx Disintegrity: Repairing the Damage caused by Trauma-Hemorrhage

内皮糖萼破坏：修复创伤出血造成的损伤

• 批准号: 10248473
• 负责人: Jillian Rouse Richter
• 金额: $ 36.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248473
• 关键词: Area; Attenuated; Basic Science; Cause of Death; Cell surface; Cessation of life; Endothelial Cells; Endothelium; Functional disorder; Glycocalyx; Glycosaminoglycans; Goals; Hemorrhage; Hemorrhagic Shock; Heparitin Sulfate; Hyaluronic Acid; Inflammation; Injury; Intestines; Kidney; Lung; Mediating; Microvascular Dysfunction; Microvascular Permeability; Multiple Organ Failure; Organ; Patients; Permeability; Research; Resuscitation; Role; Secondary to; Signal Pathway; Trauma; Traumatic injury; body system; heparanase; innovation; mortality; new therapeutic target; organ injury; prevent; programs; repaired; response; translational research program; translational study

PROJECT SUMMARY/ABSTRACT The aim of this R35 application is to develop a high quality, translational research program in inflammation- induced endothelial damage and organ dysfunction. Dysregulation of microvascular function contributes to the pathophysiology of indirect organ injury after trauma. In particular, damage to the endothelial glycocalyx occurs within minutes of traumatic injury and is associated with increased microvascular permeability resulting in multi- organ failure and increased mortality. Strategies that attenuate glycocalyx disintegrity by preventing its cleavage and/or facilitating its repair hold significant promise for minimizing microvascular dysfunction and post-traumatic organ injury. The long-term objective of our research program is to establish basic science and translational studies that focus on the identification of novel therapeutic targets that will (1) prevent glycocalyx damage, (2) repair glycocalyx integrity or (3) inhibit dysregulation of endothelial cell permeability that occurs as a result of glycocalyx disintegrity. The specific programmatic areas of focus will include studies to identify the role of heparanase in regulating glycocalyx (dis)integrity after trauma-hemorrhage and on mechanisms that mediate glycocalyx synthesis. Additionally, our proposed studies will identify signaling pathways that regulate endothelial barrier function that are effected by loss of cell surface glycosaminoglycans, heparan sulfate and hyaluronic acid, which are primary constituents of the glycocalyx layer. Our research program will focus on the endothelial cell- specific response to trauma-hemorrhage in organ systems that are most susceptible to secondary injury (e.g., kidney, lung and intestines) with the over-arching goal of determining how resuscitation strategies mediate glycocalyx-dependent mechanisms in each organ. These programmatic areas of research hold promise for significantly impacting the current resuscitation paradigm for patients in hemorrhagic shock by aiding in the discovery of novel therapeutic targets that can be used to inhibit glycocalyx dysfunction, facilitate its repair or reverse the downstream consequences of glycocalyx disintegrity.

项目概要/摘要 R35 应用的目的是开发一个高质量的炎症转化研究项目—— 诱发内皮损伤和器官功能障碍。微血管功能失调会导致 创伤后间接器官损伤的病理生理学。特别是，内皮糖萼会发生损伤 创伤性损伤后几分钟内，与微血管通透性增加有关，导致多 器官衰竭和死亡率增加。通过防止其裂解来减弱糖萼不完整性的策略 和/或促进其修复对于最大限度地减少微血管功能障碍和创伤后具有重要的希望 器官损伤。我们研究计划的长期目标是建立基础科学和转化 研究重点是识别新的治疗靶点，这些靶点将（1）防止糖萼损伤，（2） 修复糖萼完整性或（3）抑制由于以下原因而发生的内皮细胞通透性失调 糖萼不完整。具体计划的重点领域将包括确定以下作用的研究： 乙酰肝素酶在创伤出血后调节糖萼（不）完整性及其介导机制 糖萼合成。此外，我们提出的研究将确定调节内皮细胞的信号通路 屏障功能受到细胞表面糖胺聚糖、硫酸乙酰肝素和透明质酸损失的影响， 它们是糖萼层的主要成分。我们的研究计划将集中于内皮细胞- 最容易受到继发性损伤的器官系统对创伤出血的特定反应（例如， 肾、肺和肠），总体目标是确定复苏策略如何调节 每个器官中的糖萼依赖性机制。这些规划性研究领域有望 通过帮助失血性休克患者的复苏模式，显着影响当前的复苏模式 发现可用于抑制糖萼功能障碍、促进其修复或 逆转糖萼破坏的下游后果。