Targeting the Endothelium in Sepsis

描述（由申请人提供）：血管内皮通过削弱屏障功能和促进凝血来响应局部感染，以传递免疫的体液效应物和抑制微生物的传播。在全身性感染中，这些相同的保护反应变得不适应，导致弥漫性血管渗漏和弥漫性血管内凝血。我们假设败血性内皮驱动关键的疾病表现，我们寻求创新的方法来瞄准和测量这一复杂的过程。目的1将评估两种主要内皮细胞表面受体PAR1和Tie2的作用，它们的激活可促进败血症期间的炎症、血栓形成和屏障功能障碍。我们已经确定了新的药物样分子，其靶向PAR1和Tie2，并协同作用以实现面对脓毒性刺激时内皮细胞的静止。这一目标将探讨PAR1和Tie2如何在内皮细胞协同改善败血症的临床相关结果。目的2将探讨内皮如何促进败血性微血栓形成。除了评估PAR1和Tie2外，本研究还将利用遗传小鼠模型中的活体显微镜和基于细胞的新方法，对驱动败血症早期微血栓形成和晚期凝血功能障碍的内皮紊乱进行首次系统描述。目的3将寻求新的非侵入性方法来跟踪内皮对败血症的动态反应。我们已经开发出适合高通量分析的微血管屏障功能障碍和内皮血栓形成潜能的定量、实时、人性化的检测方法。我们将使用同类最大的ICU队列之一的血浆，根据临床指标和传统生物标志物测试这些检测的预测性能。我们还将探索这些检测的潜力，以衡量新的候选疗法的疗效。该应用程序将具有互补专业知识、独特资源以及生产力和协作记录的研究人员团队联合起来。我们将追求高度平行的目标，旨在通过定义基本疾病机制，测试创新的治疗策略，以及开发专注于内皮细胞的强大的新诊断工具，对败血症产生显著影响。

DESCRIPTION (provided by applicant): The vascular endothelium responds to localized infection by weakening barrier function and promoting coagulation to deliver humoral effectors of immunity and contain the spread of microbes. In systemic infection, these same protective responses become maladaptive, leading to diffuse vascular leakage and disseminated intravascular coagulation. We hypothesize that the septic endothelium drives critical disease manifestations, and we seek innovative ways to target and measure this complex process. Aim 1 will evaluate the roles of two major endothelial cell-surface receptors, PAR1 and Tie2, whose activation can promote inflammation, thrombosis, and barrier dysfunction during sepsis. We have identified novel drug-like molecules that target PAR1 and Tie2 and synergize to achieve endothelial quiescence in the face of septic stimuli. This aim will ask how PAR1 and Tie2 collaborate at the endothelium to ameliorate clinically relevant outcomes of sepsis. Aim 2 will address how the endothelium contributes to septic microthromboses. In addition to evaluating PAR1 and Tie2, this aim will provide a first-in-kind systematic description of the endothelial derangements that drive the early microthromboses and late coagulopathy of sepsis by utilizing a combination of intravital microscopy in genetic mouse models and novel cell-based approaches. Aim 3 will seek new non-invasive ways to follow the dynamic responses of the endothelium to sepsis. We have developed quantitative, real-time, humanized assays of microvascular barrier dysfunction and endothelial prothrombotic potential suitable for high-throughput analysis. Applying plasmas from one of the largest ICU cohorts of its kind, we will test the predictive performance of these assays against clinical metrics and conventional biomarkers. We will also explore the potential of these assays to gauge the efficacy of new candidate therapies. This application unites a team of investigators with complementary expertise, unique resources, and a track record of productivity and collaboration. We will pursue highly parallel aims designed to generate outstanding impact in sepsis by defining fundamental disease mechanisms, testing innovative therapeutic strategies, and developing robust new diagnostic tools focused on the endothelium.