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.
The proposed research is relevant to public health because it will provide insight into how FFP restores endothelial syndecan-1 and vascular stability, thus repairing the injured endothelium and potentially reducing death after hemorrhagic shock in injured patients. The proposed research is relevant to NIH's mission pertaining to the application of knowledge that will enhance health and reduce the burden of illness.