Syndecan shedding after trauma and hemorrhagic shock

外伤和失血性休克后多配体脱落

• 批准号: 8731257
• 负责人: Rosemary A Kozar
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731257
• 关键词: A Mouse; Adhesions; Affect; Animal Model; Biology; Blood Vessels; Cell Culture Techniques; Cell surface; Cessation of life; Clinical; Coupled; Data; Development; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Epithelial Cells; Feasibility Studies; Foundations; Fresh Frozen Plasmas; Glycocalyx; Goals; Health; Hemorrhagic Shock; Heparitin Sulfate; Human; Image; In Vitro; Injury; Knockout Mice; Knowledge; Lead; Ligands; Link; Lung; Mediator of activation protein; Mission; Modeling; Molecular; Mus; Organ; Outcome; Pathway interactions; Patients; Plasma; Play; Proteoglycan; Public Health; Research; Resuscitation; Role; Shock; Signal Transduction; Surface; Testing; Time; Tissue Inhibitor of Metalloproteinase-3; Transfusion; Transgenic Mice; Trauma; Vertebral column; Work; adenoviral-mediated; base; burden of illness; cadherin 5; clinically relevant; fibroglycan; heparin proteoglycan; improved; in vivo; inhibitor/antagonist; injured; innovation; insight; lung injury; mortality; mouse model; mutant; novel; novel strategies; public health relevance; receptor; reconstitution; repaired; restoration; syndecan

DESCRIPTION (provided by applicant): There is a fundamental gap in the understanding between syndecan-1 (sdc-1) shedding and mortality in severely injured patients in hemorrhagic shock (HS). Additionally, our knowledge of the precise cellular and molecular mechanisms responsible for reduced mortality by the early use of fresh frozen plasma (FFP) after HS is limited. While the long term goal is to understand the molecular link between HS-induced sdc-1 shedding and vascular instability, the objective of the current application is to identify how sdc- shedding contributes to vascular instability after HS and how shed sdc-1 is reconstituted by FFP. The central hypothesis is that 1) HS induces sdc-1 shedding from the endothelium; 2) sdc-1 shedding leads to vascular instability and organ injury; and 3) FFP based resuscitation repairs vascular instability and organ injury by restoring sdc-1 expression. This hypothesis is based on preliminary data which demonstrates the feasibility of studying syndecan biology in a model of HS. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Examine HS-induced sdc-1 ectodomain shedding and restitution; 2) Investigate the mechanism of sdc-1 shedding and restitution after HS; and 3) Investigate the specific contribution of endothelial syndecan-1 to restoration of vascular stability after HS. The approaches are innovative because they focus for the first time on shedding of sdc-1 after hemorrhagic shock and its restitution by FFP based resuscitationon. The proposed research is significant because it is expected to advance the understanding of HS-induced sdc-1 shedding and vascular hyperpermeability and to provide a mechanistic foundation to guide the use of FFP. The conclusions from this work are expected to not only help guide current therapies, but facilitate the development of novel strategies to reduce HS-related deaths after severe injury.

描述（由申请人提供）：在失血性休克（HS）严重受伤患者中，对syndecan-1（sdc-1）脱落和死亡率之间的理解存在根本性差距。此外，我们对HS后早期使用新鲜冷冻血浆（FFP）降低死亡率的确切细胞和分子机制的了解有限。虽然长期目标是了解HS诱导的sdc-1脱落和血管不稳定性之间的分子联系，但本申请的目的是鉴定sdc-脱落如何在HS后促成血管不稳定性以及脱落的sdc-1如何通过FFP重建。中心假设是1）HS诱导sdc-1从内皮脱落; 2）sdc-1脱落导致血管不稳定和器官损伤;以及3）基于FFP的复苏通过恢复sdc-1表达来修复血管不稳定和器官损伤。这一假设是基于初步的数据，这表明在HS模型中研究syndecan生物学的可行性。在强有力的初步数据的指导下，将通过追求三个具体目标来检验该假设：1）检查HS诱导的sdc-1胞外域脱落和恢复; 2）研究HS后sdc-1脱落和恢复的机制;以及3）研究内皮多配体蛋白聚糖-1对HS后血管稳定性恢复的具体贡献。这些方法是创新的，因为它们首次关注了失血性休克后sdc-1的脱落及其通过基于FFP的复苏的恢复。这项研究具有重要意义，因为它有望促进对HS诱导的sdc-1脱落和血管通透性增高的理解，并为指导FFP的使用提供机制基础。这项工作的结论预计不仅有助于指导目前的治疗，而且有助于开发新的策略，以减少严重损伤后HS相关的死亡。