Syndecan shedding after trauma and hemorrhagic shock

描述（由申请人提供）：在失血性休克（HS）重症患者中，syndecan-1 （sdc-1）的脱落与死亡率之间存在根本性的认识差距。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脱落与血管不稳定之间的分子联系，但当前应用的目标是确定sdc-脱落如何导致HS后血管不稳定，以及脱落的sdc-1如何被FFP重建。主要假设是：1)HS诱导内皮细胞脱落sdc-1；2) sdc-1脱落导致血管不稳定和器官损伤；3)基于FFP的复苏通过恢复sdc-1表达修复血管不稳定和器官损伤。这一假设是基于初步数据，证明了在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，这一假设将通过追求三个具体目标来验证：1)检查hs诱导的sdc-1外畴脱落和恢复；2)研究HS后sdc-1脱落和恢复的机制；3)研究内皮细胞syndecan-1在HS后血管稳定性恢复中的具体作用。这些方法是创新的，因为它们首次关注失血性休克后sdc-1的脱落以及基于FFP的复苏对其的恢复。该研究具有重要意义，因为它有望促进对hs诱导的sdc-1脱落和血管高通透性的理解，并为指导FFP的使用提供机制基础。这项工作的结论不仅有助于指导当前的治疗方法，而且有助于开发新的策略来减少严重损伤后hs相关的死亡。

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.