Targeting the Endothelium in Sepsis

针对脓毒症中的内皮细胞

基本信息

批准号：
8927679
负责人：
Robert C Flaumenhaft
金额：
$ 83.64万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8927679
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 prevention Inflammation Inflammatory Injury Link Lung Measures Mediator of activation protein Methods 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 targeted treatment tool

项目摘要

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并促进凝结以提供免疫力的体液效应子并包含微生物的扩散，从而对局部感染做出反应。在全身感染中，这些相同的保护性反应变得不良适应性，导致弥漫性血管泄漏和弥散性血管内凝血。我们假设化脓性内皮驱动关键疾病表现，我们寻求创新的方法来靶向和衡量这一复杂过程。 AIM 1将评估两个主要的内皮细胞表面受体PAR1和TIE2的作用，它们的激活可以促进败血症期间的炎症，血栓形成和屏障功能障碍。我们已经确定了靶向PAR1和TIE2的新型药物样分子，并在面对败血性刺激的情况下达到了内皮静止。这个目标将询问PAR1和TIE2如何在内皮上进行协作，以改善败血症的临床相关结果。 AIM 2将解决内皮如何对化粪池微塑料贡献。除了评估PAR1和TIE2外，该目标还将提供对内皮扰动的首个系统描述，这些杂物可以通过利用遗传学显微镜在遗传小鼠模型和基于新颖的细胞方法中的弹性显微镜组合来驱动早期的微骨和晚期脓毒症。 AIM 3将寻求新的非侵入性方法来遵循内皮对败血症的动态反应。我们已经开发了微血管屏障功能障碍和适用于高通量分析的内皮实质性障碍的定量，实时人性化测定。利用来自同类ICU队列之一的等离子体，我们将测试这些测定法对临床指标和常规生物标志物的预测性能。我们还将探讨这些测定法的潜力，以评估新候选疗法的功效。该应用程序将一个调查员团队团结在一起，具有互补的专业知识，独特的资源以及生产力和协作的记录。我们将实现高度平行的目标，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针对内皮细胞的强大新诊断工具，从而产生败血症的出色影响。