Free Radicals Influence the Pathogenesis of Venous Thrombosis

描述（由申请人提供）：深静脉血栓形成（DVT）在这个国家仍然是一个严重的卫生保健问题，每年有超过250,000名患者受到影响，每年至少有200,000名患者被诊断为肺栓塞（PE），尽管这些数字是保守的。美国医疗保健系统每年仅用于静脉血栓急性治疗的费用就超过数十亿美元。目前的研究表明，血管内皮的缺氧和生化损伤是多种心血管疾病发病的一个因素。内皮功能障碍是一个术语，用于确定几种病理条件，可导致改变凝血，炎症，受损血管生长和血管重塑。这一过程与氧化应激的增加有关，氧化应激是炎症过程的促进剂。

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.