Free Radicals Influence the Pathogenesis of Venous Thrombosis

自由基影响静脉血栓形成的发病机制

• 批准号: 7788823
• 负责人: Daniel Durant Myers
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7788823
• 关键词: Acute; Address; Advisory Committees; Affect; Animal Model; Applications Grants; Area; Biochemical; Biology; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cellular biology; Chemical Injury; Coagulation Process; Country; Deep Vein Thrombosis; Diagnosis; Free Radicals; Functional disorder; Genes; Grant; Growth; Healthcare; Healthcare Systems; Hypoxia; Inflammation; Inflammation Mediators; Inflammatory; Injury; Laboratories; Lead; Ligands; Mentors; Molecular Biology; Mus; Natural History; Oxidative Stress; Pathogenesis; Patients; Phase; Play; Process; Pulmonary Embolism; Research; Research Training; Role; Selectins; Thromboplastin; Thrombosis; Thrombus; Time Study; Treatment Cost; United States; Up-Regulation; Vascular Endothelium; Vascular remodeling; Veins; Venous; Venous Thrombosis; Wild Type Mouse; cytokine; defined contribution; in vivo; member; mouse model; promoter; research study

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.

描述（由申请人提供）：在这个国家，深静脉血栓形成（DVT）仍然是一个严重的医疗保健问题，尽管这些数字是保守的，但每年有超过25万名患者每年受到肺栓塞（PE）的诊断至少20万名患者。每年仅用于静脉血栓形成的急性治疗，美国医疗保健系统的治疗费用超过数十亿美元。目前，研究表明，血管内皮的缺氧和生化损伤是几种心血管疾病发病机理的一个因素。内皮功能障碍是一个用于识别多种病理状况的术语，HAT会导致凝血，炎症，血管生长受损和血管重塑的改变。该过程与氧化应激的增加有关，这是炎症过程的启动子。 我们的研究假设是，由于体内自由基损伤，静脉内皮的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HAT抑制选择蛋白配体和TF活性将减少炎症和静脉血栓形成。我们将以两个特定的目的解决这一假设：特定目的I：确定静脉血栓形成小鼠模型中自由基损伤的自然历史。 特定目标II：确定影响静脉血栓形成发病机理的自由基损伤的机制。我们将使用完全缺乏选择素配体活性缺乏转基因的小鼠和表达非常低水平的TF水平的小鼠来定义这些机制来定义这些机制。这些小鼠将与也经历了自由基损伤的野生型（WT）小鼠进行比较。这些实验将定义自由基在静脉血栓形成的发病机理中的作用。 该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，细胞生物学和凝结生物学通过频繁的教学会话与原发性课程 导师Thomas W. Wakefield博士和我的研究咨询委员会成员。这笔赠款的第二阶段将重点是完成赠款的具体目标，并允许候选人发展独立的研究领域。