The applicant will test in this grant the hypothesis that acute traumatic coagulopahty is primarily caused by tissue hypoperfusion resulting in a complement mediated activation and subsequent depletion of the protein C pathway (AIMS 1 and 2). While the in vitro and in vivo approaches detailed in AIMS 1 and 2 will provide important mechanistic information regarding acute traumatic coagulopathy, the coagulation system is of such complexity to be completely visualized using the traditional cascade. The applicant will test the hypothesis that new techniques in network topology and dynamic modeling will allow for superior visualization and predict changes in the structure and function of the protein C system after trauma (AIM 3). Specifically he will first use a mouse model of trauma/shock to determine the timing and mechanism of perturbations in protein C after trauma and hypoperfusion. Secondly, he will use both the in vivo mouse model as well as an in vitro model of endothelial cell ischemia reperfusion to test the role of complement in activation of protein C after trauma and shock. Third, he will utilize a network representation of the protein C pathway as well as a newly constructed dynamic model of protein C to model in silico the protein C pathway after trauma and shock. The information obtained in these experiments will have important therapeutic significance in humans. The preliminary data from trauma patients that form the rationale for this grant application indicates that coagulation and complement abnormalities begin early after trauma, and are associated with significant morbidity and increased mortality. Thus understanding the molecular and systems level mechanisms associated with post traumatic coagulation and complement abnormalities may provide new avenues for therapy in trauma patients. The concerns here are that the model does replicate elements of what patients present with clinically. The typical trauma patient has not suffered only a loss on intravascular volume but has associated tissue injury. Damaged tissue represents an important part of the injury burden and contributes to the post injury dyshomeostasis. How this will impact the interpretation of the experimental model output needs to be directly considered by the applicant.
Aim 3 entails dynamic modeling based on the results of Aim 1 and 2 data and as such is an interesting approach. The question is how will it be validated as reflective of what occurs in trauma patients?
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