Mechanisms for Deep Vein Thrombosis following Stroke

项目摘要/摘要 静脉血栓栓塞症(VTE)，包括深静脉血栓形成(DVT)和肺栓塞(PE) 对发病率和死亡率的巨大影响。急性缺血性中风和衰老被认为是重大风险 发展危及生命的VTE赛事。而预防性抗凝可降低此类患者的VTE发生率。 高危患者，他们只能预防大约一半的预期VTE事件，并且与 极大的出血风险，表明迫切需要新的安全的辅助治疗来减少VTE 负担。近年来，有令人信服的证据表明，中性粒细胞参与了中性粒细胞的启动和 深静脉血栓形成的发病机制。在初步研究中，我们发现中风会增加DVT的风险， 在小鼠和人类中，人和小鼠中风后中性粒细胞上整合素α9表达上调 它有助于中性粒细胞与内皮细胞的黏附。我们还观察到中性粒细胞特异性α9-/- 小鼠对深静脉血栓的易感性较低。我们的中心假设是，中性粒细胞整合素α9促进深静脉血栓形成。 老龄化和中风的背景。该提案的总体目标是评估下列机制 中性粒细胞整合素α-9促进深静脉血栓形成，同时探讨其相关性和治疗潜力 中风后深静脉血栓形成。在目标1中，我们将确定中性粒细胞整合素α9在促进深静脉血栓形成中的机制作用。 中风和衰老的背景。我们将评估潜在的分子机制， 卒中后中性粒细胞黏附与深静脉血栓形成为了最佳的科学严谨性和确保结果的重现性， 我们将考虑年龄、性别以及有无缺血性中风来检验这一假说。我们将使用 临床相关模型(DVT的细丝/栓塞性卒中模型和下腔静脉狭窄模型)。在目标2中，我们将 确定抑制整合素α9对静脉血栓形成的翻译影响。我们会用好的 在小鼠模型中鉴定了抗整合素α9抗体。通过利用对照和对照的全血样本 在缺血性卒中患者中，我们将在体外测定整合素α9抑制对静脉幅度的影响 血栓形成。该项目将提供强有力的证据，证明中性粒细胞整合素α9在以下情况下促进深静脉血栓形成 中风和衰老。该项目的较长期影响将是促进抗整合素α9的开发 可与现有血栓预防方案结合使用以减轻静脉血栓栓塞术负担的治疗方法 在这样的高危人群中。

Project Summary/Abstract Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have an immense impact on morbidity and mortality. Acute ischemic stroke and aging are considered significant risk for developing life-threatening VTE events. While prophylactic anticoagulation reduces the rates of VTE in such high-risk patients, they only prevent approximately half of the expected VTE events and are associated with significant risk of bleeding, suggesting the critical need for novel and safe adjuvant treatments to reduce VTE burden. In recent years, compelling evidence has emerged that implicates neutrophils in the initiation and pathogenesis of deep vein thrombosis (DVT). In pilot studies, we found that stroke increases the risk of DVT, both in mice and humans and integrin α9 is upregulated on neutrophils following stroke in humans and in mice and it contributes to adhesion of neutrophils to the endothelium. We also observe that neutrophil specific α9-/- mice were less susceptible to DVT. Our central hypothesis is that neutrophil integrin α9 promotes DVT in the context of aging and stroke. The overall objective of the proposal is to evaluate the mechanisms by which neutrophil integrin α9 promotes DVT while exploring its relevance and therapeutic potential in reducing poststroke DVT. In aim 1, we will determine the mechanistic role of neutrophil integrin α9 in promoting DVT in the context of stroke and aging. We will evaluate underlying molecular mechanisms that contributes to poststroke neutrophil adhesion and DVT. For optimal scientific rigor and to ensure reproducibility of the results, we will test this hypothesis considering age, sex and the presence and absence of ischemic stroke. We will use clinically relevant models (filament/embolic stroke models and IVC stenosis models for DVT). In aim 2, we will determine the translational impact of inhibiting integrin α9 on venous thrombosis. We will use well characterized anti-integrin α9 antibody in mouse models. By utilizing whole blood samples from controls and patients with ischemic stroke, we will determine in vitro effect of integrin α9 inhibition on magnitude of venous thrombosis. This project will provide robust evidence that neutrophil integrin α9 promotes DVT in the context of stroke and aging. A longer-term impact of the project will be facilitation of the development of anti-integrin α9 therapeutics that can be used in combination with current thromboprophylaxis regimens to reduce VTE burden in such high-risk population.