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: 7408128
• 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/7408128
• 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; Condition; Country; Deep Vein Thrombosis; Diagnosis; Free Radicals; Functional disorder; Genes; Grant; Growth; Healthcare; Healthcare Systems; Hypoxia; Inflammation; Inflammatory; Injury; Laboratories; Lead; Ligands; Mediator of activation protein; 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; Transcriptional Activation; 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）：深静脉血栓形成（DVT）仍然是该国严重的医疗保健问题，每年有超过250，000例患者受到影响，每年至少有200，000例诊断为肺栓塞（PE），尽管这些数字是保守的。美国卫生保健系统每年仅用于静脉血栓形成的急性治疗的治疗费用就超过数十亿美元。目前，研究表明，缺氧和生化损伤血管内皮细胞是一个因素，在一些心血管疾病的发病机制。内皮功能障碍是一个术语，用于识别可导致凝血改变、炎症、血管生长受损和血管重塑的几种病理状况。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。 我们的研究假设是体内自由基损伤导致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。我们还假设选择素配体和TF活性的抑制将减少炎症和静脉血栓形成。我们将解决这一假设有两个具体的目标：具体目标一：以确定在静脉血栓形成的小鼠模型中的自由基损伤的自然历史。 目的二：探讨自由基损伤对静脉血栓形成的影响机制。我们将通过改变静脉壁炎症的水平来定义这些机制，这些静脉壁炎症是使用选择素配体活性完全缺乏的转基因小鼠和表达非常低水平TF的小鼠进行的定时研究。将这些小鼠与也经历自由基损伤的野生型（WT）小鼠进行比较。这些实验将明确自由基在静脉血栓形成发病机制中的作用。 这项赠款建议由两个阶段组成。第一阶段将包括以下方面的研究培训： 分子生物学，细胞生物学和凝血生物学，通过经常与小学教学会议， 导师托马斯W.韦克菲尔德和我的研究咨询委员会的成员。该补助金的第二阶段将侧重于完成补助金的具体目标，并允许候选人开发独立的研究领域。