Contact Activation and Infection

项目摘要 我们的研究项目旨在测试我们的中心假设，即接触激活系统 有助于导致血管功能障碍、凝血酶生成和 特定病原体全身细菌攻击时的炎症反应。 尽管有有效的抗生素可用，脓毒症仍然是一种普遍的临床综合征和显著的 由一系列快速进展带来的严重住院发病率和死亡率的原因 在暴露于并随后发生系统性感染时发生的动态分子和细胞事件 某些病原体。使问题复杂化的是多重耐药细菌的日益流行 病原体。目前，经过半个多世纪的研究、药物开发和无数 临床试验，目前仍没有FDA批准的上市药物专门用于治疗糖尿病 败血症。脓毒症可导致多器官系统衰竭，包括血管调节功能障碍、组织不良 严重脓毒症的特征是灌流、浮肿和全身性低血压。通过触发 心肺和血管崩溃，即使有可用的支持和抗生素，它也往往是致命的 治疗。脓毒症可能伴有弥散性血管内凝血(DIC)，这可能导致 血栓形成和因消耗性凝血障碍引起的出血。我们关注的是联系人的激活 系统，因为1)凝血因子XII的激活似乎存在因果关系 以及某些形式的脓毒症的不良预后，以及2)将接触激活系统作为一种 治疗方法不太可能对宿主造成有害后果，如出血。我们会 研究接触激活系统中的分子步骤在糖尿病的发生发展中的作用 实验性细菌感染，活体内。我们将定义FXII(目标1)及其促凝剂的作用 底物FXI(目标2)，并翻译我们的体外机制研究，以表征病理作用 细菌感染的两种不同的狒狒模型中的接触激活。 我们项目的潜在翻译相关性将是确定安全和可用药 接触激活系统中的分子靶点和机制。我们的研究最终可能 为开发可安全受益的选择性接触激活抑制剂提供理论依据 有可能导致接触系统激活的病原体感染或有感染风险的患者。

Project Summary Our research project is designed to test our central hypothesis that the contact activation system contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during systemic bacterial challenge by specific pathogens. Despite the availability of effective antibiotics, sepsis remains a prevalent clinical syndrome and significant cause of severe in-hospital morbidity and mortality, brought about by a sequence of rapidly advancing dynamic molecular and cellular events that occur upon exposure to and subsequent systemic infection by certain pathogens. Complicating the problem is the increasing prevalence of multiresistant bacterial pathogens. At present, after more than half a century of research, drug development, and countless clinical trials, there are still no FDA-approved marketed drugs specifically indicated for the treatment of sepsis. Sepsis can lead to multiple organ system failure, including failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension, which are hallmarks of severe sepsis. By triggering cardiopulmonary and vascular collapse, it is often lethal even with available supportive and antibiotic treatments. Sepsis may be accompanied by disseminated intravascular coagulation (DIC), which can lead to both thrombosis and bleeding due to the consumptive coagulopathy. We focus on the contact activation system, because 1) there appears to be a causal relationship between activation of coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation system as a therapeutic approach is unlikely to have detrimental consequences for the host such as bleeding. We will study the role of the molecular steps in the contact activation system in the development and outcome of experimental bacterial infection, in vivo. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and translate our mechanistic in vitro studies to characterize the pathological role of contact activation in two distinct baboon models of bacterial infection. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation system. Our research may ultimately provide rationale for the development of selective contact activation inhibitors that could safely benefit patients that have or are at risk of infections by pathogens that can cause contact system activation.