Mechanisms in Blood Clotting

摘要 总体愿景是对调节血液凝结系统的机制有一个详细的了解， 目的是阐明凝血机制在止血和止血方面的不同作用 血栓形成。概念框架是，人类血栓性疾病是由一种原本具有保护性的 机制(免疫血栓形成)出了问题。在这种观点下，血管损伤后的止血是由 使血液迅速暴露于预先存在的天然促凝血剂，如组织因子和胶原蛋白 在人体内普遍存在，导致止血栓迅速形成。另一方面， 免疫血栓形成可能由损伤相关蛋白的详细阐述而触发和/或大大增强 分子模式(DAMP)和病原体相关分子模式(PAMP)。一个重要的概念是 其中许多促进免疫血栓形成的PAMP和阻滞剂是潜在的治疗靶点 应该很少或根本不参与正常止血。为了实现这一愿景，我们需要有一个 更好地从机制上理解是什么调节了血液凝固反应，尤其是我们需要 识别和了解导致血栓形成和凝血疾病的湿气。拟议的工作将集中在 在这一总体概念框架内的三个一般领域：阐明促凝剂 阴离子聚合物，如聚磷酸盐(Polyp)和核酸，触发调节血液凝固和 炎症；确定控制组织因子/因子VIIa复合体功能的关键结构细节； 并详细了解磷脂双层如何调节血液凝结反应。这些 研究将建立在我们以前在这一领域取得的成功的基础上，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.