The complement system links platelet activation to inflammation

炎症和血栓形成过程之间的相互作用日益增加。 被认为与各种疾病的发病机制有关的。这是一个明显的例子 相互作用在败血症中很明显，败血症是对感染的一种全身炎症反应。脓毒症是 美国非心脏重症监护病房的主要死亡原因，以及 微血管血栓形成是脓毒症的重要并发症。问题的一个方面是 脓毒症的炎症反应涉及补体系统，补体系统是 先天免疫反应。最近的数据表明，补体系统可以提供 炎症和血栓形成之间的联系；这个应用程序将有助于理解 参与这些相互作用的机制，特别强调败血症。中环 假说是补体系统的血小板相关成分提供了一种联系 脓毒症的炎症和血栓形成之间的关系。该提案将利用基因靶向 补体缺陷小鼠及其相关对照的体外和体内血小板功能评价 活着。体外实验涉及到血小板聚集的测量，以及 区分固有的血小板缺陷和补体因子沉积的影响 血小板。活体实验将利用微血管的活体显微镜模型 血栓形成，这使得评估血小板-微血管相互作用的动力学在 实时的。一些实验将使用被动转移血小板来确定 血小板结合的补体受体足以介导该受体的作用 微血管血栓形成。提出了两个目标：目标1将决定哪一个补语 补体系统的途径和血小板相关成分介导异常 补体缺乏小鼠的血小板功能。目标2将确定以下组件的作用 补体系统在实验性脓毒症微血管血栓形成中的作用完成 这些目标将扩大对补充性制度作为联系 炎症和血栓形成，重点是败血症。

The interactions between the processes of inflammation and thrombosis are increasingly recognized as relevant to the pathogenesis of various diseases. A striking example of these interactions is evident in sepsis, a systemic inflammatory response to an infection. Sepsis is the leading cause of death in non-cardiac intensive care units in the United States, and microvascular thrombosis is a significant complication in sepsis. One aspect of the inflammatory response in sepsis involves the complement system, an integral part of the innate immune response. Recent data demonstrate that the complement system may provide a link between inflammation and thrombosis; this application will help understand the mechanisms involved in these interactions, with a particular emphasis on sepsis. The central hypothesis is that platelet-associated components of the complement system provide a link between inflammation and thrombosis in sepsis. The proposal will utilize genetically targeted complement deficient mice and their relevant controls to assess platelet function ex vivo and in vivo. Ex vivo experiments involve measures of platelet aggregation, and protocols to distinguish intrinsic platelet defects from effects due to complement factor deposition on platelets. In vivo experiments will utilize an intravital microscopy model of microvascular thrombosis, which allows assessment of the kinetics of platelet-microvessel interactions in real-time. Some experiments will use passive transfer of platelets to determine whether a platelet-bound complement receptor is sufficient to mediate the role of this receptor in microvascular thrombosis. Two aims are proposed: Aim 1 will determine which complement pathways and platelet-associated components of the complement system mediate abnormal platelet function in complement deficient mice. Aim 2 will determine the role of components of the complement system in microvascular thrombosis in experimental sepsis. Completion of these aims will broaden understanding of the role of the complement system as a link between inflammation and thrombosis, with an emphasis on sepsis.