Free Radicals Influence the Pathogenesis of Venous Thrombosis

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DESCRIPTION (provided by applicant): Deep venous thrombosis (DVT) remains a serious health care problem in this country, with over 250,000 patients affected annually and at least 200,000 diagnosed yearly with pulmonary embolism (PE), although these figures are conservative. Treatment costs to the United States health care system exceed billions of dollars per year just for the acute treatment of venous thrombosis. Presently, research suggests that hypoxic and biochemical injury to vascular endothelium is a factor in the pathogenesis of several cardiovascular diseases. Endothelial dysfunction is a term used to identify several pathological conditions hat can lead to altered coagulation, inflammation, impaired vascular growth, and vascular remodeling. This process is associated with an increase in oxidative stress which is a promoter of the inflammatory process. Our research hypothesis is that gene dysregulation of the venous endothelial due to free radical injury in vivo promotes venous thrombogenesis by activating selectin ligands and tissue factor (TF). We also hypothesize hat the inhibition of selectin ligand and TF activity will decrease inflammation and venous thrombogenesis. We will address this hypotheses with two specific aims: Specific Aim I: To determine the natural history of free radical injury in a mouse model of venous thrombosis. Specific Aim II: To determine the mechanisms of free radical injury that influences the pathogenesis of venous thrombosis. We will define these mechanisms by varying the levels of vein wall inflammation in timed studies using genetically modified mice completely deficient in selectin ligand activity and mice expressing very low levels of TF. These mice will be compared to wild-type (WT) mice that have also undergone free radical injury. These experiments will define the role of free radicals in the pathogenesis of venous thrombosis. This grant proposal is composed of two phases. The first phase will consist of research training in molecular biology, cell biology and coagulation biology through frequent didactic sessions with primary mentor Dr. Thomas W. Wakefield and members of my research advisory committee. The second phase of this grant will focus on completion of the specific aims of the grant and allow for the candidate to develop independent areas of research.