Trauma is a serious health problem in the United States and the leading cause of death in young people. Trauma causes tissue injury, resulting in disruption of normal barriers, leading to dysfunction of physiologic systems and organs. Significant damage to the vasculature results in abnormalities in blood flow and coagulation that further compromise vital organ function. Tissue factor (TF) is a transmembrane glycoprotein that is normally expressed in epithelial cells, glial cells, mucosal cells and adventitia. TF binds to factor VII and active VIIa to trigger the extrinsic and intrinsic coagulation pathways. Activation of TF expression in cells where it is normally not expressed, such as endothelium, results in thrombosis and coagulation abnormalities. Inhibition of TF activity has been shown to increase survival in animal models of sepsis. Inappropriate activity of the coagulation cascade during trauma may be, in part due, to a potent activator such as TF. The proposed research focuses on studying the expression and activity of TF in trauma. The major hypothesis to be tested is that TF expression is an important mechanism of endothelial dysfunction and tissue damage in trauma.
The specific aims of this proposal involve four areas of investigation.
The first aim i s to characterize TF gene expression following trauma. This goal will be accomplished by utilizing a well-recognized model of soft tissue trauma and murine traumatic shock (Noble-Collip drum trauma). After soft tissue trauma is induced in anesthetized rats, vital signs will be monitored and TF expression measured in vital organ mRNA, tissue extracts, and plasma. Coagulation activity will be measured with standard assays.
The second aim will be to determine the relationship between TF and two other important mediators of leukocyte-endothelial-platelet interaction, P-selectin and nitric oxide (NO). This goal will be achieved by using Noble-Collip drum trauma, as well as cultured monocytes, macrophages, and vascular cells, and determining TF expression while manipulating experimental conditions with NO and P-selectin agonists and antagonists.
The third aim will be to investigate the effect of inhibition of TF activity in traumatic shock by administering tissue factor pathway inhibitor, TF antibody and inhibitors of early activation of TF gene transcription.
The fourth aim i s to analyze the regulatory mechanisms of the induction of TF gene expression related to trauma by administering analogs of potential TF regulatory factors to our experimental models. The long-term objective is to determine if modulation of TF subsequent to trauma changes the natural course of traumatic shock.
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