Characterization of Coagulation Factor-platelet Interactions: Role of FXI

项目总结： 动脉粥样硬化仍然是大多数心血管疾病的根本原因 死亡率。我们的总体假设是两种血液接触系统蛋白的病理性激活，因子 (F)XI和FXII，介导血小板-内皮细胞相互作用以促进炎症和白细胞的运输 在动脉粥样硬化斑块形成的实验模型中。我们的初步研究将接触 对炎症的激活和对血小板的激活表明FXI的药物靶向可以 减少血管炎症、动脉粥样硬化及其心血管并发症，并将更加安全 而不是传统的抗凝剂或血小板抑制药，后者具有致命出血的巨大风险。 到目前为止，我们的工作和发现为开发更安全的抗血栓药物打开了一扇窗 战略。这个项目将采取一个新的方向来研究接触激活是否会增加血小板- 内皮细胞的相互作用，白细胞的募集和渗透，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为分子开发工具的能力基础上 细胞相互作用的成像，接触激活的新抑制物的创造，以及理性和 负责从体外研究到体内小鼠和非人类灵长类动物模型的使用和翻译 疾病。在目标1中，我们将确定FXI在激活血小板促进动脉粥样硬化形成中的作用。我们会 验证我们的假设，即依赖FXI的血小板激活促进白细胞对炎症的募集 内皮细胞。在目标2中，我们将确定FXII在动脉粥样硬化中促进炎症的作用。我们 将检验我们的假设，即FXI激活FXII和FXI诱导细胞因子和补体生成 促进炎症以促进动脉粥样硬化的物质。我们将把我们的体外机制研究 明确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。 我们项目的翻译相关性将是潜在的安全分子靶标的识别和 可支持开发新的药理学方法以解决 进行性动脉粥样硬化问题。

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.