Syndecan shedding after trauma and hemorrhagic shock

描述（由申请人提供）：对于失血性休克 (HS) 重伤患者的 syndecan-1 (sdc-1) 脱落和死亡率之间的理解存在根本性差距。此外，我们对热射病后早期使用新鲜冰冻血浆 (FFP) 降低死亡率的精确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 如何通过 FFP 重建。中心假设是 1) HS 诱导 sdc-1 从内皮细胞脱落； 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 表达来修复血管不稳定和器官损伤。该假设基于初步数据，该数据证明了在 HS 模型中研究多配体生物学的可行性。在强有力的初步数据的指导下，该假设将通过追求三个具体目标进行检验：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； 3) 研究内皮细胞 syndecan-1 对 HS 后血管稳定性恢复的具体贡献。这些方法具有创新性，因为它们首次关注失血性休克后 sdc-1 的脱落及其通过基于 FFP 的复苏的恢复。这项研究意义重大，因为它有望增进对 HS 诱导的 sdc-1 脱落和血管通透性过高的理解，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当前的治疗方法，而且有助于制定新策略，以减少严重损伤后与热射病相关的死亡。

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.