Characterization of Coagulation Factor-platelet Interactions: Role of FXI

凝血因子-血小板相互作用的表征：FXI 的作用

基本信息

批准号：
10133119
负责人：
Owen J McCarty
金额：
$ 70.07万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133119
关键词：
Address Adhesions Animal Model Anti-Cytokine Therapy Anti-Inflammatory Agents Antibodies Anticoagulants Antiplatelet Drugs Antisense Oligonucleotides Arterial Fatty Streak Arteries Arteriosclerosis Arthritis Atherosclerosis Attenuated Binding Biomedical Research Blood Blood Coagulation Factor Blood Platelets Blood Proteins Blood Vessels Blood coagulation Bradykinin Cardiovascular Diseases Cardiovascular system Cell Communication Cessation of life Chronic Complement Complement Activation Complex Country Data Dedications Deposition Development Disease model Endothelial Cells Endothelium Event Experimental Models Factor XI Factor XI Deficiency Factor XII Generations Goals Grant Heart failure Hemorrhage Hemostatic function Human Hypertension In Vitro Incidence Industrialization Infiltration Inflammation Inflammatory Kininogenase Leukocyte Trafficking Leukocytes Link Mediating Modeling Molecular Target Mus Myocardial Infarction Pathogenesis Pathologic Pathologic Processes Pathway interactions Patients Pharmacology Physiological Plasminogen Activator Inhibitor 1 Platelet Activation Platelet Count measurement Platelet Inhibitors Primates Proteins Research Resolution Risk Role Safety Schedule Serpins Severities Signal Transduction Stroke System Systemic Inflammatory Response Syndrome TFPI Testing Thrombin Thrombopoietin Thrombosis Thrombus Translating Translations Ultrasonography Work atherogenesis circulating biomarkers contrast enhanced cytokine endothelial dysfunction genetic risk factor granulocyte imaging platform in vivo inflammatory marker inhibitor/antagonist migration molecular imaging monocyte mortality new therapeutic target nonhuman primate novel phase II trial prevent programs recruit response thrombotic tool traditional therapy treatment risk vascular inflammation

项目摘要

Project Summary: Atherosclerosis remains the underlying cause of the majority of cardiovascular diseases contributing to mortality. Our overall hypothesis is that pathological activation of two blood contact system proteins, factor (F) XI and FXII, mediate platelet-endothelial interactions to promote inflammation and leukocyte trafficking in experimental models of atherosclerotic plaque formation. Our preliminary studies linking contact activation to inflammation and platelet activation suggest that pharmacological targeting of FXI could reduce vascular inflammation, atherogenesis, and its cardiovascular complications, and would be safer than traditional anticoagulants or platelet inhibitors, which carry a significant risk of fatal bleeding. Our work and findings to date have opened the window towards the development of safer antithrombotic strategies. This program will take a new direction to study whether contact activation increases platelet- endothelial cell interactions, leukocyte recruitment and infiltration, and inflammation to promote atherosclerotic plaque formation. This program will build on our ability to develop tools for molecular imaging of cell interactions, the creation of novel inhibitors of contact activation, and rational and responsible use of and translation from in vitro studies to in vivo mouse and non-human primate models of disease. In Aim 1 we will determine the role of FXI in activating platelets to promote atherogenesis. We will test our hypothesis that FXI-dependent platelet activation promotes recruitment of leukocytes to inflamed endothelium. In Aim 2 we will determine the role of FXII in promoting inflammation in atherogenesis. We will test our hypothesis that FXII activation of and by FXI induces cytokine and complement generation that contribute to inflammation to promote atherogenesis. We will translate our mechanistic in vitro studies to define the pathological role of contact activation in 2 distinct animal models of atherogenesis. The translational relevance of our project will be the potential identification of safe molecular targets and mechanisms that could support the development of novel pharmacological approaches to address the problem of progressive atherosclerosis.

项目摘要：动脉粥样硬化仍然是大多数心血管疾病的根本原因死亡。我们的总体假设是两个血接触系统蛋白的病理激活，因子（f）XI和FXII，介导血小板 - 内皮相互作用，以促进炎症和白细胞运输在动脉粥样硬化斑块形成的实验模型中。我们的初步研究将联系联系激活炎症和血小板激活表明FXI的药理学靶向减少血管炎症，动脉粥样硬化及其心血管并发症，并将更安全比传统的抗凝剂或血小板抑制剂，这些抑制剂具有严重的致命出血风险。迄今为止，我们的工作和发现打开了开发更安全的抗血栓形成的窗口策略。该程序将迈出一个新的方向来研究接触激活是否增加了血小板 - 内皮细胞相互作用，白细胞募集和浸润以及炎症以促进动脉粥样硬化斑块形成。该程序将基于我们开发分子工具的能力细胞相互作用的成像，新型接触激活的抑制剂以及有理由和负责使用和翻译从体外研究到体内小鼠和非人类灵长类动物模型疾病。在AIM 1中，我们将确定FXI在激活血小板以促进动脉粥样硬化中的作用。我们将检验我们的假设，即FXI依赖性血小板激活促进白细胞募集到发炎内皮。在AIM 2中，我们将确定FXII在促进炎症中的作用。我们将检验我们的假设，即FXI的激活和通过FXI诱导细胞因子和补体产生这有助于炎症促进动脉粥样硬化。我们将翻译我们的机械体外研究在2种不同的动脉粥样硬化模型中，接触激活的病理作用。我们项目的翻译相关性将是对安全分子靶标的潜在识别和可以支持开发新的药理学方法来解决的机制进行性动脉粥样硬化的问题。