Free Radicals Influence the Pathogenesis of Venous Thrombosis

描述(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医疗保健问题，每年有超过25万名患者受到影响，每年至少有20万人被诊断为肺栓塞(PE)，尽管这些数字是保守的。仅静脉血栓的急性治疗，美国医疗保健系统每年的治疗费用就超过数十亿美元。目前，研究表明血管内皮细胞的缺氧性和生化性损伤是多种心血管疾病的发病因素之一。内皮功能障碍是一个术语，用来识别几种可能导致凝血改变、炎症、血管生长受损和血管重塑的病理状况。这一过程与氧化应激增加有关，氧化应激是炎症过程的促进剂。 我们的研究假设是体内自由基损伤引起的静脉内皮细胞基因失调通过激活选择素配体和组织因子(Tf)促进静脉血栓形成。我们还假设，抑制选择素配体和TF活性将减少炎症和静脉血栓形成。我们将用两个特定的目标来解决这一假说：特定的目标I：确定静脉血栓形成小鼠模型中自由基损伤的自然历史。目的II：探讨自由基损伤影响静脉血栓形成的机制。我们将在使用完全缺乏选择素配体活性的转基因小鼠和表达非常低水平的转铁蛋白的小鼠的定时研究中，通过改变静脉壁炎症的水平来定义这些机制。这些小鼠将与同样经历过自由基损伤的野生型(WT)小鼠进行比较。这些实验将确定自由基在静脉血栓形成发病机制中的作用。 这项赠款提案由两个阶段组成。第一阶段将包括研究培训 分子生物学、细胞生物学和凝血生物学 导师托马斯·W·韦克菲尔德博士和我的研究咨询委员会成员。这笔赠款的第二阶段将侧重于完成赠款的具体目标，并允许候选人发展独立的研究领域。

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.