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Mechanisms for Deep Vein Thrombosis following Stroke

中风后深静脉血栓形成的机制

基本信息

批准号：
10443141
负责人：
Nirav Dhanesha
金额：
$ 44.87万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
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/10443141
关键词：
Acute Adhesions Adjuvant 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 Pharmacology 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 post stroke prevent prophylactic sex stroke model stroke patient stroke therapy therapeutic target translational impact venous thromboembolism

项目摘要

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/文摘