Novel Therapeutic Targets for Venous Thromboembolism

描述(由申请人提供)： 静脉血栓栓塞症(VTE；DVT/PE)是一个全国性的健康问题，每年发生90多万例，死亡30多万人，超过乳腺癌和艾滋病的总和。在这个国家，每年VTE总病例的发病率超过心肌梗塞和中风的数量，而与VTE相关的死亡的发生率超过与心肌梗死或中风相关的死亡的数量。随着人口老龄化，静脉血栓栓塞症的发病率一直在上升。虽然静脉血栓栓塞症的标准治疗是抗凝(在某些情况下是溶栓治疗)，但这种治疗具有显著的出血潜力，在高达30%的病例中与血栓进展有关，并且无法预防血栓形成后综合征的长期后遗症、腿部疼痛和肿胀。因此，目前静脉血栓栓塞症的治疗并不能产生最佳的结果。我们和其他人已经证明，静脉血栓栓塞症会发生显著的炎症反应，这种炎症对血栓形成和静脉壁纤维化都有很大影响。特别是，P-选择素及其配体受体PSGL-1似乎与静脉血栓的形成密切相关，因为循环中P-选择素水平高的动物会产生大的静脉血栓，而P-选择素基因缺失的动物会产生较小的血栓。尽管VWF在静脉血栓形成中的作用尚不清楚，但静脉血栓的形成既受血小板和白细胞黏附的影响，也受这些因素之间的相互作用的影响，这些相互作用在很大程度上是由VWF介导的。目前的建议涉及VWF和P-选择素在啮齿动物静脉血栓形成模型基础研究中的作用，在已建立的髂静脉血栓的灵长类动物模型中评估VWF和P-选择素的新适配子抑制剂，并评估基于VWF和P-选择素的生物标记物在患者静脉血栓形成诊断和随访中的作用。这项工作将为这类药物最终临床应用于静脉血栓栓塞症的预防和治疗奠定基础。在这个提案的结论中，我们将明确VWF在静脉血栓形成中的作用，开发新的VWF和P-选择素适配子，在静脉血栓模型中测试这些适配子，并确定新的生物标记物的临床价值。公共卫生相关性：项目描述：该提案将确定VWF和P-选择素在不同动物模型和患者的静脉血栓形成中的作用。我们还将开发针对这些分子的新药物，用于预防和治疗静脉血栓形成。

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.