Mechanisms for Deep Vein Thrombosis following Stroke

中风后深静脉血栓形成的机制

• 批准号: 10687268
• 负责人: Nirav Dhanesha
• 金额: $ 45.3万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687268
• 关键词: Acute; Adhesions; Adjuvant Therapy; Affect; Age; Aging; Antibodies; Anticoagulants; Anticoagulation; Blood; Blood Platelets; Blood specimen; Bone Marrow Transplantation; CASP1 gene; Cell Adhesion Molecules; Custom; Data; Deep Vein Thrombosis; Development; Endothelial Cells; Endothelium; Ensure; Event; Experimental Models; Filament; Genetic; Glycocalyx; Hemorrhage; Human; IL8RB gene; In Vitro; Incidence; Infection; Inferior vena cava structure; Inflammasome; Integrin Inhibition; Integrins; Ischemic Stroke; Knowledge; Leukocytes; Life; Lymphocyte; Microfluidic Microchips; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Neutropenia; Outcome; PTK2 gene; Pathogenesis; Patients; Pilot Projects; Pre-Clinical Model; Predisposition; Prophylactic treatment; Pulmonary Embolism; Regimen; Reproducibility of Results; Risk; Risk Factors; Role; Severities; Signal Pathway; Stenosis; Stroke; Testing; Therapeutic; Thrombosis; Veins; Venous; Venous Thrombosis; Whole Blood; aged; clinically relevant; comorbidity; embolic stroke; extracellular; high risk; high risk population; in vivo evaluation; inhibitor; integrin alpha9; male; monocyte; mortality; mouse model; neutrophil; new therapeutic target; novel; patient population; pharmacologic; post stroke; prevent; prophylactic; sex; stroke model; stroke patient; stroke therapy; therapeutic target; translational impact; venous thromboembolism

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.

项目总结/摘要 静脉血栓栓塞（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。急性缺血性卒中和衰老被认为是显著风险 发生危及生命的静脉血栓栓塞事件虽然预防性抗凝可降低此类患者的VTE发生率， 对于高危患者，它们只能预防大约一半的预期VTE事件，并且与 出血风险显著，提示迫切需要新型安全的辅助治疗以减少VTE 负担近年来，已经出现了令人信服的证据，表明中性粒细胞在启动和 深静脉血栓形成（DVT）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，在人类和小鼠中风后，中性粒细胞上的整合素α9上调 并且它有助于嗜中性粒细胞粘附到内皮。我们还观察到中性粒细胞特异性α9-/- 小鼠对DVT不太敏感。我们的中心假设是，中性粒细胞整合素α9促进DVT， 衰老和中风的背景。该提案的总体目标是评估 中性粒细胞整合素α9促进DVT，同时探索其在减少DVT中的相关性和治疗潜力。 卒中后DVT。在目的1中，我们将确定中性粒细胞整合素α9在促进DVT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，有助于 卒中后中性粒细胞粘附和DVT。为了达到最佳的科学严谨性并确保结果的可重复性， 我们将根据年龄、性别和是否存在缺血性卒中来检验这一假设。我们将使用 临床相关模型（用于DVT的细丝/栓塞性卒中模型和IVC狭窄模型）。在目标2中，我们 确定抑制整合素α9对静脉血栓形成的翻译影响。我们会好好利用 在小鼠模型中表征抗整联蛋白α9抗体。通过使用来自对照的全血样本， 对于缺血性卒中患者，我们将在体外确定整合素α9抑制对静脉血栓形成的程度的影响。 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DVT： 中风和衰老该项目的长期影响将促进抗整合素α9的开发 可与当前血栓预防方案联合使用以降低VTE负荷的治疗方法 这样的高危人群。