Mechanisms in Blood Clotting

摘要 总体愿景是建立一个详细的了解机制，调节血液凝固系统， 目的是阐明凝血机制在止血和凝血功能方面的差异， 血栓形成概念框架是，人类血栓性疾病是由其他保护性疾病引起的。 机制（免疫血栓形成）出错。在这种观点中，血管损伤后的止血是由 血液迅速暴露于预先存在的天然促凝剂，如组织因子和胶原蛋白， 在全身普遍存在，并诱导快速形成止血栓。另一方面，在一项研究中， 免疫血栓形成很可能是由损伤相关的 分子模式（DAMPs）和病原体相关分子模式（PAMPs）。一个重要的概念是 许多驱动免疫血栓形成的PAMP和DAMP是潜在的治疗靶点， 应该很少或不参与正常止血。为了实现这一愿景，我们需要 更好地了解调节血液凝固反应的机制，特别是我们需要 识别和理解驱动血栓形成和凝血病的DAMP。拟议工作将侧重于 这一总体概念框架内的三大领域：阐明促凝血剂 阴离子聚合物如聚磷酸盐（polyP）和核酸触发调节血液凝固， 确定控制组织因子/因子VIIa复合物功能的关键结构细节; 并详细了解磷脂双层如何调节凝血反应。这些 研究将建立在我们先前在这一领域取得的成功之上，并将推动这一领域的发展。

Abstract The overall vision is to create a detailed understanding of mechanisms that regulate the blood clotting system, with a goal of elucidating the aspects of the clotting machinery that function differentially in hemostasis versus thrombosis. The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism (immunothrombosis) gone awry. In this view, hemostasis following vascular injury is driven by the prompt exposure of blood to preexisting, natural procoagulants such as tissue factor and collagen that are ubiquitous throughout the body and that induce rapid formation of hemostatic plugs. On the other hand, immunothrombosis is likely triggered and/or greatly enhanced by the elaboration of damage-associated molecular patterns (DAMPs) and pathogen-associate molecular patterns (PAMPs). An important concept is that many of these PAMPs and DAMPs that drive immunothrombosis are potential therapeutic targets that should have little or no involvement in normal hemostasis. In order to achieve this vision, we need to have a much better mechanistic understanding of what regulates blood clotting reactions, and in particular we need to identify and understand the DAMPs that drive thrombosis and coagulopathies. The proposed work will focus on three general areas within this general conceptual framework: elucidating mechanisms by which procoagulant anionic polymers such as polyphosphate (polyP) and nucleic acids trigger regulate blood clotting and inflammation; identifying key structural details that control the function of the tissue factor/factor VIIa complex; and achieving a detailed understanding of how phospholipid bilayers regulate blood clotting reactions. These studies will build on our prior success in this area and will advance the field.