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 (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 250,000 名患者受到影响，每年至少有 200,000 名患者被诊断患有肺栓塞 (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的急性治疗的治疗费用就超过数十亿美元。目前，研究表明血管内皮的缺氧和生化损伤是多种心血管疾病发病机制的一个因素。内皮功能障碍是一个术语，用于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的增加有关，氧化应激是炎症过程的促进者。 我们的研究假设是体内自由基损伤导致的静脉内皮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。我们将通过两个具体目标来解决这一假设： 具体目标 I：确定静脉血栓形成小鼠模型中自由基损伤的自然史。 具体目标二：确定自由基损伤影响静脉血栓形成的机制。我们将通过在定时研究中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 TF 的小鼠来改变静脉壁炎症水平来定义这些机制。这些小鼠将与也遭受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。 该拨款提案由两个阶段组成。第一阶段将包括研究培训 通过与小学经常进行的教学课程，学习分子生物学、细胞生物学和凝血生物学 导师 Thomas W. Wakefield 博士和我的研究顾问委员会成员。该资助的第二阶段将侧重于完成资助的具体目标，并允许候选人开发独立的研究领域。