Targeting the Endothelium in Sepsis

针对脓毒症中的内皮细胞

• 批准号: 8800323
• 负责人: Robert C Flaumenhaft
• 金额: $ 87.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800323
• 关键词: ANGPT2 gene; Acute; Address; Angiopoietin-2; Anthrax disease; Binding; Biological Assay; Biological Markers; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Cell Adhesion Molecules; Cell Surface Receptors; Cell physiology; Cells; Characteristics; Clinical; Coagulation Process; Collaborations; Collection; Combined Modality Therapy; Complex; Critical Illness; Cytoprotection; Diffuse; Disease; Disease susceptibility; Disseminated Intravascular Coagulation; Effectiveness; Endothelial Cells; Endothelium; Endotoxemia; Environment; Enzymes; Extravasation; Face; Fibrin; Floods; Fluorescent Probes; Focal Infection; Functional disorder; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Programming; Hemorrhage; Human; Immunity; Infection; Infection prevention; Inflammation; Inflammatory; Injury; Link; Lung; Measures; Mediator of activation protein; Methods; Metric; Microbe; Modeling; Molecular; Organ; Outcome; P-Selectin; PAR-1 Receptor; Pathway interactions; Patients; Performance; Perfusion; Pharmaceutical Preparations; Phenotype; Plasma; Process; Productivity; Protein Disulfide Isomerase; Proteins; Publishing; Research Personnel; Resources; Role; Sampling; Sepsis; Septic Shock; Signal Transduction; Specificity; Stimulus; Susceptibility Gene; Systemic infection; Testing; Therapeutic; Thrombosis; Thrombus; Time; Tissues; Vascular Endothelium; Vascular System; Virulence Factors; Work; adverse outcome; anergy; base; candidate marker; clinical application; clinically relevant; cohort; design; endothelial dysfunction; genome-wide; high throughput analysis; high throughput screening; improved; in vivo; inhibitor/antagonist; innovation; intravital microscopy; miniaturize; mortality; mouse model; novel; novel diagnostics; novel therapeutic intervention; prevent; receptor; response; screening; septic; small molecule; small molecule libraries; tool

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.

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并遏制微生物的传播。在全身感染中，这些相同的保护性反应变得适应不良，导致弥漫性血管渗漏和弥散性血管内凝血。我们假设脓毒症内皮细胞导致了严重的疾病表现，并且我们寻求创新的方法来瞄准和测量这一复杂的过程。目标 1 将评估两种主要内皮细胞表面受体 PAR1 和 Tie2 的作用，它们的激活可促进脓毒症期​​间的炎症、血栓形成和屏障功能障碍。我们已经鉴定出新型药物样分子，它们以 PAR1 和 Tie2 为靶点，并在面对脓毒症刺激时协同作用以实现内皮静止。该目标将询问 PAR1 和 Tie2 如何在内皮细胞中协作以改善脓毒症的临床相关结果。目标 2 将解决内皮细胞如何导致脓毒性微血栓。除了评估 PAR1 和 Tie2 之外，该目标还将通过结合遗传小鼠模型中的活体显微镜和新颖的基于细胞的方法，对驱动脓毒症早期微血栓和晚期凝血病的内皮紊乱提供首次系统描述。目标 3 将寻求新的非侵入性方法来追踪内皮细胞对脓毒症的动态反应。我们开发了适用于高通量分析的微血管屏障功能障碍和内皮血栓形成潜力的定量、实时、人性化检测方法。我们将使用来自同类最大的 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测定的预测性能。我们还将探索这些测定法的潜力，以衡量新候选疗法的功效。该应用程序将一组具有互补专业知识、独特资源以及生产力和协作记录的研究人员团结在一起。我们将追求高度并行的目标，旨在通过定义基本疾病机制、测试创新治疗策略和开发针对内皮的强大的新诊断工具，对脓毒症产生显着影响。