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: 10027428
• 负责人: Jillian Rouse Richter
• 金额: $ 34.01万
• 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/10027428
• 关键词: Area; Attenuated; Basic Science; Cause of Death; Cell surface; Cessation of life; Endothelial Cells; Endothelium; Failure; Functional disorder; Glycocalyx; Glycosaminoglycans; Goals; Hemorrhage; Hemorrhagic Shock; Heparitin Sulfate; Hyaluronic Acid; Inflammation; Injury; Intestines; Kidney; Lung; Mediating; Microvascular Dysfunction; Microvascular Permeability; 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.

项目总结/文摘