Novel Therapeutic Targets for Venous Thromboembolism

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，每年发生超过90万例，每年死亡超过30万例，超过乳腺癌和艾滋病的总和。在这个国家，每年VTE总病例的发生率超过心肌梗死和卒中的数量，而VTE相关死亡的发生率超过心肌梗死相关死亡或卒中相关死亡的数量。随着人口的老龄化，静脉血栓栓塞的发病率也在不断上升。尽管静脉血栓栓塞的标准治疗是抗凝（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，与高达30%的病例中的血栓进展相关，并且不能预防血栓后综合征、腿部疼痛和肿胀的长期后遗症。因此，目前静脉血栓栓塞症的治疗并没有产生最佳结果。我们和其他人已经证明，静脉血栓栓塞会发生显著的炎症反应，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，因为具有高循环水平的P-选择素的动物产生大的静脉血栓，而具有P-选择素基因缺失的动物产生较小的血栓。虽然VWF在静脉血栓栓塞中的作用尚不清楚，但静脉血栓形成受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，这些相互作用主要由VWF介导。目前的提案解决了VWF和P-选择素在静脉血栓形成的啮齿动物模型中的基础研究中的作用，在充分建立的髂静脉血栓形成的灵长类动物模型中评价了VWF和P-选择素的新适体抑制剂，并评价了基于VWF和P-选择素的生物标志物用于患者静脉血栓形成的诊断和随访。这项工作将为此类药物在预防和治疗静脉血栓栓塞症方面的最终临床应用奠定基础。在这项建议的结论，我们将定义VWF在静脉血栓形成中的作用，开发新的适配体VWF和P-选择素，测试这些适配体在静脉血栓形成模型，并确定新的生物标志物的临床价值。 公共卫生相关性：项目叙述：该建议将确定VWF和P-选择素在各种动物模型和患者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.