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

• 批准号: 7793389
• 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
• 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/7793389
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This research program will focus on sepsis, which is caused by the body's response to a severe infection. That response, or inflammation, can cause serious complications, including blood clots in very small blood vessels that may result in organ dysfunction. Sepsis is the most common cause of death in medical intensive care units in the United States, including the VA system. There is no specific treatment for these complications of sepsis, probably because it is unclear how they occur. The proposed work will help clarify how these clots form, by studying the role of an important aspect of inflammation, known as the complement system. This work may result in new treatments for the small blood clots and organ dysfunction in sepsis, with the long-term goal of improving the outcome of patients with this devastating condition.

描述（由申请人提供）： 人们越来越认识到炎症和血栓形成过程之间的相互作用与各种疾病的发病机制有关。这些相互作用的一个引人注目的例子是败血症，这是一种对感染的全身炎症反应。脓毒症是美国非心脏重症监护室的首要死因，而微血管血栓形成是脓毒症的一个重要并发症。脓毒症炎症反应的一方面涉及补体系统，它是先天免疫反应的一个组成部分。最近的数据表明，补体系统可能提供炎症和血栓形成之间的联系。该应用程序将有助于了解这些相互作用所涉及的机制，特别是脓毒症。中心假设是补体系统的血小板相关成分在败血症中的炎症和血栓形成之间提供了联系。该提案将利用基因靶向补体缺陷小鼠及其相关对照来评估离体和体内血小板功能。离体实验涉及血小板聚集的测量，以及区分固有血小板缺陷和补体因子沉积在血小板上的影响的方案。体内实验将利用微血管血栓形成的活体显微镜模型，该模型可以实时评估血小板-微血管相互作用的动力学。一些实验将使用血小板的被动转移来确定血小板结合的补体受体是否足以介导该受体在微血管血栓形成中的作用。提出了两个目标：目标 1 将确定哪些补体途径和补体系统的血小板相关成分介导补体缺陷小鼠中异常的血小板功能。目标 2 将确定补体系统成分在实验性脓毒症微血管血栓形成中的作用。这些目标的完成将加深对补体系统作为炎症和血栓形成之间的联系的作用的理解，重点是脓毒症。 公共卫生相关性： 该研究计划将重点关注败血症，这是由身体对严重感染的反应引起的。这种反应或炎症可能会导致严重的并发症，包括非常小的血管中出现血栓，可能导致器官功能障碍。脓毒症是美国医疗重症监护病房（包括退伍军人管理局系统）最常见的死亡原因。对于脓毒症的这些并发症没有具体的治疗方法，可能是因为尚不清楚它们是如何发生的。拟议的工作将通过研究炎症的一个重要方面（称为补体系统）的作用，帮助阐明这些凝块是如何形成的。这项工作可能会为脓毒症中的小血栓和器官功能障碍带来新的治疗方法，长期目标是改善患有这种破坏性疾病的患者的预后。