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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：
9764125
负责人：
Owen J McCarty
金额：
$ 70.76万
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/9764125
关键词：
Address Adhesions Animal Model Anti-Cytokine Therapy Anti-inflammatory 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 Phase II Clinical Trials 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 prevent programs recruit response 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.

项目概要：动脉粥样硬化仍然是大多数心血管疾病的根本原因， mortality.我们的总体假设是两种血液接触系统蛋白质的病理激活， (F)XI和FXII介导血小板-内皮相互作用，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。我们的初步研究表明炎症激活和血小板激活表明，FXI的药理学靶向作用可减少血管炎症、动脉粥样硬化及其心血管并发症，与传统的抗凝剂或血小板抑制剂相比，后者存在致命出血的重大风险。我们的工作和发现，迄今已打开窗口，朝着发展更安全的抗血栓战略布局该项目将为研究接触性活化是否增加血小板- 内皮细胞相互作用、白细胞募集和浸润以及炎症，动脉粥样硬化斑块形成。该计划将建立在我们开发分子工具的能力之上。细胞相互作用的成像，接触激活的新型抑制剂的产生，以及合理的和负责任地使用体外研究并将其转化为体内小鼠和非人灵长类动物模型，疾病在目标1中，我们将确定FXI在激活血小板以促进动脉粥样硬化形成中的作用。我们将检验我们的假设，即FXI依赖性血小板活化促进白细胞向炎症细胞的募集，内皮细胞在目标2中，我们将确定FXII在动脉粥样硬化形成中促进炎症的作用。我们将检验我们的假设，即FXI的FXII激活和FXI的激活诱导细胞因子和补体的产生从而促进动脉粥样硬化形成。我们将把我们的机械体外研究在2种不同的动脉粥样硬化动物模型中确定接触激活的病理作用。我们项目的翻译相关性将是潜在的安全分子靶点的鉴定，机制，可以支持开发新的药理学方法，以解决进行性动脉粥样硬化的问题。