Characterization of Coagulation Factor-platelet Interactions: Role of FXI

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， 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， 而传统的抗凝剂或血小板抑制剂具有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激活诱导细胞因子和补体产生 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。

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.