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：
10386792
负责人：
Owen J McCarty
金额：
$ 70.11万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386792
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 Work atherogenesis circulating biomarkers contrast enhanced cytokine endothelial dysfunction genetic risk factor granulocyte imaging platform in vivo inflammatory marker inhibitor migration molecular imaging monocyte mortality new therapeutic target nonhuman primate novel phase II trial prevent programs recruit response thrombotic tool traditional therapy treatment risk ultrasound 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死亡。我们的总体假设是两种血液接触系统蛋白（因子）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动脉粥样硬化斑块形成的实验模型。我们的初步研究链接联系方式炎症激活和血小板激活表明 FXI 的药理学靶向可以减少血管炎症、动脉粥样硬化及其心血管并发症，更安全与传统的抗凝剂或血小板抑制剂相比，后者具有显着的致命出血风险。迄今为止，我们的工作和发现为开发更安全的抗血栓药物打开了窗口策略。该计划将采取新的方向来研究接触激活是否会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促进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创建，以及合理和负责任地使用体外研究并将其转化为体内小鼠和非人类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 依赖性血小板激活促进白细胞募集至发炎部位内皮细胞。在目标 2 中，我们将确定 FXII 在促进动脉粥样硬化炎症中的作用。我们将检验我们的假设，即 FXI 的 FXII 激活以及 FXI 的 FXII 激活会诱导细胞因子和补体生成有助于炎症促进动脉粥样硬化形成。我们将转化我们的体外机制研究定义接触激活在两种不同的动脉粥样硬化动物模型中的病理作用。我们项目的转化相关性将是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这一问题的机制进行性动脉粥样硬化的问题。

项目成果

期刊论文数量（145）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Promotion of experimental thrombus formation by the procoagulant activity of breast cancer cells.

DOI：
10.1088/1478-3975/8/1/015014
发表时间：
2011-02
期刊：
Physical biology
影响因子：
2
作者：
Berny-Lang MA;Aslan JE;Tormoen GW;Patel IA;Bock PE;Gruber A;McCarty OJ
通讯作者：
McCarty OJ

Rho GTPases in platelet function.

DOI：
10.1111/jth.12051
发表时间：
2013-01
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Aslan JE;McCarty OJ
通讯作者：
McCarty OJ

Measurement of single cell refractive index, dry mass, volume, and density using a transillumination microscope.

DOI：
10.1103/physrevlett.109.118105
发表时间：
2012-09-14
期刊：
Physical review letters
影响因子：
8.6
作者：
Phillips KG;Jacques SL;McCarty OJ
通讯作者：
McCarty OJ

Gammaherpesvirus latency induces antibody-associated thrombocytopenia in mice.

DOI：
10.1016/j.jaut.2012.11.005
发表时间：
2013-05
期刊：
Journal of autoimmunity
影响因子：
12.8
作者：
Freeman ML;Burkum CE;Lanzer KG;Roberts AD;Pinkevych M;Itakura A;Kummer LW;Szaba FM;Davenport MP;McCarty OJ;Woodland DL;Smiley ST;Blackman MA
通讯作者：
Blackman MA

The role of carrier number on the procoagulant activity of tissue factor in blood and plasma.