Novel Therapeutic Targets for Venous Thromboembolism

静脉血栓栓塞的新治疗靶点

• 批准号: 7904134
• 负责人: DENISA D WAGNER
• 金额: $ 72.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904134
• 关键词: Address; Adhesions; Aging; Animal Model; Animals; Biological Markers; Blood Platelets; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Country; Deep Vein Thrombosis; Diagnosis; Elements; Enoxaparin; Fibrin fragment D; Fibrosis; Genes; Health; Hemorrhage; Human; Iliac Vein; In Vitro; Incidence; Inflammation; Inflammatory Response; Ischemia; Leukocytes; Ligands; Low-Molecular-Weight Heparin; Mediating; Modeling; Mus; Myocardial Infarction; New Agents; Outcome; P-Selectin; P-selectin ligand protein; Pain in lower limb; Patients; Platelet Inhibitors; Population; Postphlebitic Syndrome; Preparation; Prevention; Primates; Process; Prophylactic treatment; Reperfusion Therapy; Risk Factors; Rodent Model; Role; Stroke; Swelling; Testing; Thromboembolism; Thrombolytic Therapy; Thrombosis; Thrombus; Veins; Venous; Venous Thrombosis; Work; aptamer; base; cell type; clinical application; follow-up; improved; inhibitor/antagonist; malignant breast neoplasm; new therapeutic target; novel; novel therapeutics; prevent; public health relevance; receptor; standard care

DESCRIPTION (provided by applicant): Venous thromboembolism (VTE; DVT/PE) is a national health concern, with an occurrence of over 900,000 cases per year and over 300,000 deaths per year, more than breast cancer and AIDs combined. The incidence of total cases of VTE exceeds the number of myocardial infarctions and strokes in this country yearly, while the incidence of VTE related deaths exceeds the number of myocardial infarction related deaths or stroke-related deaths. The incidence of VTE has been increasing with the aging of the population. Although the standard treatment of venous thromboembolism is anti-coagulation (and in some cases thrombolytic therapy), such treatment has significant bleeding potential, is associated with thrombus progression in up to 30% of cases, and does not prevent the long-term sequelae of the postthrombotic syndrome, leg pain and swelling. Thus, current treatment for venous thromboembolism does not result in optimal outcomes. We and others have demonstrated that a significant inflammatory response occurs with venous thromboembolism and that this inflammation has great influence over both thrombosis and vein wall fibrosis. Specifically, P-selectin and its ligand receptor PSGL-1, appear to be strongly related to venous thrombogenesis, as animals with high circulating level of P-selectin produce large venous thrombi, while animals having gene deleted for P-selectin produce smaller thrombi. Although the role of VWF in venous thromboembolism is unclear, venous thrombogenesis is influenced both by platelet and leukocyte adhesion and interactions between these elements, interactions which are largely mediated by VWF. The current proposal addresses the role of VWF and P-selectin in basic studies in rodent models of venous thrombosis, evaluates new aptamer inhibitors to VWF and P-selectin in a well established primate model of iliac vein thrombosis, and evaluates biomarkers based on VWF and P- selectin for the diagnosis and follow-up of venous thrombosis in patients. This work will be the basis for eventual clinical application of such agents to the prophylaxis and treatment of venous thromboembolism. At the conclusion of this proposal, we will have defined the role of VWF in venous thrombosis, developed new aptamers to VWF and P-selectin, tested these aptamers in models of venous thrombosis, and determined the clinical value of new biomarkers. public health relevance: Project Narrative: This proposal will determine the role of VWF and P-selectin in venous thrombosis in various animal models and in patients. We will also develop new agents to target these molecules for the prevention and treatment of venous thrombosis.

描述（由申请人提供）： 静脉血栓栓塞（VTE; DVT/PE）是一个全国性的健康问题，每年发生900,000例，每年发生300,000多人死亡，超过乳腺癌和艾滋病的总和。每年，VTE总病例的发生率超过了该国的心肌梗死和中风的数量，而与VTE相关的死亡的发生率超过了与心肌梗塞相关的死亡或中风相关的死亡人数。随着人群的衰老，VTE的发生率一直在增加。尽管静脉血栓栓塞的标准治疗方法是抗凝（并且在某些情况下溶栓治疗），但这种治疗具有明显的出血潜力，与多达30％的病例的血栓进展有关，并且不能阻止肉毒术后的长期后遗症，腿部疼痛，腿部疼痛和肿胀。因此，当前对静脉血栓栓塞的治疗不会导致最佳结局。我们和其他人已经证明，静脉血栓栓塞发生了明显的炎症反应，并且这种炎症对血栓形成和静脉壁纤维化都有很大的影响。具体而言，P-选择素及其配体受体PSGL-1似乎与静脉血栓形成密切相关，因为P-Selectin水平较高的动物会产生大型静脉血栓，而在P-链球菌中删除基因的动物会产生较小的血栓。尽管VWF在静脉血栓栓塞中的作用尚不清楚，但静脉血栓形成受到血小板和白细胞粘附以及这些元素之间的相互作用的影响，这些相互作用在很大程度上由VWF介导。当前的提议解决了VWF和P-选择素在基础研究中的作用，在静脉血栓形成的啮齿动物模型中，评估了对VWF和P-选择素的新适时抑制剂在伊利亚西亚静脉血栓形成的良好的灵长类动物模型中，并评估基于VWF和P-Selectin的生物标记物，用于诊断和随访。这项工作将是此类药物在预防和治疗静脉血栓栓塞的最终临床应用的基础。在该提案的结论中，我们将定义VWF在静脉血栓形成中的作用，开发了对VWF和P-选择素的新适体，在静脉血栓形成模型中测试了这些适体，并确定了新生物标志物的临床价值。 公共卫生相关性：项目叙述：该提案将决定VWF和P-选择素在各种动物模型和患者中静脉血栓形成中的作用。我们还将开发新的药物来靶向这些分子，以预防和治疗静脉血栓形成。