The complement system links platelet activation to inflammation

补体系统将血小板激活与炎症联系起来

基本信息

批准号：
8195599
负责人：
ROLANDO E RUMBAUT
金额：
--
依托单位：
MICHAEL E DEBAKEY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195599
关键词：
Abnormal Platelet Alternative Complement Pathway Bacterial Toxins Binding Blood Clot Blood Platelets Blood Vessels Blood coagulation C5a anaphylatoxin receptor Cause of Death Coagulation Process Complement Complement Factor H Complement Receptor Complication Data Defect Deposition Disease Employee Strikes Functional disorder Funding Goals Immune response Infection Inflammation Inflammation Process Inflammatory Inflammatory Response Integrins Intensive Care Units Kinetics Laboratories Link Measures Mediating Mediator of activation protein Medical Modeling Morbidity - disease rate Mus Organ Outcome Pathogenesis Patients Plasma Platelet Activation Platelet aggregation Process Protocols documentation Research Role Sepsis Surface System Therapeutic Thrombosis Time United States Veterans Work complement deficiency complement pathway complement system improved in vivo intravital microscopy mortality new therapeutic target programs public health relevance receptor research study response

项目摘要

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.

炎症和血栓形成过程之间的相互作用日益增多被认为与多种疾病的发病机制有关。其中一个引人注目的例子脓毒症是一种对感染的全身炎症反应，这种相互作用在脓毒症中很明显。败血症是美国非心脏重症监护病房的主要原因，以及微血管血栓形成是脓毒症的一个重要并发症。一方面脓毒症的炎症反应涉及补体系统，它是免疫系统的一个组成部分。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；该应用程序将有助于理解这些相互作用涉及的机制，特别是脓毒症。中央假设补体系统的血小板相关成分提供了一种联系脓毒症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，以评估离体和体内血小板功能体内。离体实验涉及血小板聚集的测量以及实验方案区分固有血小板缺陷和补体因子沉积的影响血小板。体内实验将利用微血管的活体显微镜模型血栓形成，可以评估血小板-微血管相互作用的动力学即时的。一些实验将使用血小板的被动转移来确定是否血小板结合补体受体足以介导该受体在微血管血栓形成。提出了两个目标：目标 1 将确定哪个补充补体系统的途径和血小板相关成分介导异常补体缺陷小鼠的血小板功能。目标 2 将确定以下组件的作用实验性脓毒症微血管血栓形成中的补体系统。完成这些目标将加深对补体系统作为两者之间的联系的作用的理解。炎症和血栓形成，重点是败血症。