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

项目总结/摘要 该R35应用程序的目的是开发一个高质量的炎症转化研究计划- 导致内皮损伤和器官功能障碍。微血管功能的失调有助于 创伤后间接器官损伤的病理生理学。尤其是内皮糖萼的损伤 在创伤性损伤的几分钟内，并与微血管通透性增加有关，导致多- 器官衰竭和死亡率增加。通过防止其切割来减弱糖萼不完整性的策略 和/或促进其修复对于最小化微血管功能障碍 器官损伤我们的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）预防糖萼损伤，（2） 修复糖萼的完整性或（3）抑制内皮细胞通透性的失调， 糖萼不完整。具体的方案重点领域将包括开展研究， 乙酰肝素酶调节创伤出血后糖萼（不完整）及其机制 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在内皮细胞- 对最易继发性损伤的器官系统中的创伤出血的特异性反应（例如， 肾、肺和肠），其首要目标是确定复苏策略如何介导 糖萼依赖机制在每个器官。这些研究的纲领性领域有希望为 显著影响了目前失血性休克患者的复苏模式， 发现新的治疗靶点，可用于抑制糖萼功能障碍，促进其修复或 逆转糖萼不完整的下游后果。

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.