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Tissue Factor, Flow, and Platelet Adhesion/Aggregation on Activated Endothelium

活化内皮上的组织因子、血流和血小板粘附/聚集

基本信息

批准号：
8049138
负责人：
Eric Franklin Grabowski
金额：
$ 39.83万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049138
关键词：
ADAMTS Adhesions Adhesives Affect Antibodies Antiphospholipid Antibodies Apoptosis Appearance Arteries Attention Bacterial Toxins Beds Binding Blood Blood Platelets Blood Vessels Blood flow Cell Adhesion Molecules Cell membrane Cell secretion Cell surface Cells Cessation of life Childhood Cleaved cell Coagulation Process Collagen Coma Coronary artery Culture Media Deposition Disease Down-Regulation Endothelial Cells Endothelium Enhancers Ensure Epidemic Epithelial Cells Escherichia coli Escherichia coli EHEC Factor VIIa Fibrin Fibrinogen Fostering Glass Glycosylphosphatidylinositols Health Hemolytic-Uremic Syndrome Hour Human Image Impairment Incubated Inflammatory Integrin beta3 Integrins Intercellular adhesion molecule 1 Interleukin-1 Interruption Intestines Kidney Kidney Failure Lead Leukocytes Link Measurement Mediating Membrane Messenger RNA Modeling Necrosis Organ P-Selectin Pathway interactions Peptide Hydrolases Phenotype Phosphatidylserines Phospholipids Play Process Production Proteins Recombinants Relative (related person)Reporting Resolution Role Route Seizures Selectins Shiga Toxin Shiga-Like Toxin I Site Slide Stress Surface System TFPI TNF gene Testing Therapeutic Therapeutic Intervention Thick Thrombin Thromboplastin Thrombosis Thrombus Tissues Toxin United States Up-Regulation Vascular Endothelium Video Microscopy Vitronectin Receptors Whole Blood Work arteriole cell injury cytokine digital exposed human population foodborne granulocyte in vitro Model in vivo inhibitor/antagonist mRNA Stability monolayer oxidized low density lipoprotein receptor research study shear stress von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): In vivo, platelet adhesion/aggregation on activated endothelium may proceed via upregulation of endothelial cell (EC) molecules adhesive for platelets, especially 1v23 (the vitronectin receptor), ICAM-1, P-selectin, and ultra large von Willebrand factor (vWF) strings, accompanied and followed by tissue factor (TF)-driven mural platelet thrombosis in arteries or arterioles. The necessary EC activation may arise via several routes, including oxidized low density lipoproteins, bacterial toxins, and/or cytokines. The present work will test the hypothesis and paradigm that upregulation of these adhesion molecules permits the initiation of platelet adhesion/aggregation on endothelium, a process which is then amplified by both EC-associated TF and blood- borne TF. Blood-borne TF exists in the form of microparticles derived from leukocytes, platelets, and ECs. Upregulation of the EC-associated type of TF may take place by a variety of mechanisms, studied here: a) increases in TF mRNA stability and/or decreases in TFPI mRNA stability, b) enhancement of phosphatidylserine on the EC membrane outer leaflet, and c) reduction in the regulatory ability of EC-associated TFPI. We further hypothesize that mural platelet thrombi, in turn, slow blood flow sufficiently to allow activated endothelium to assume an even more procoagulant phenotype. A prime example of this paradigm is the epidemic childhood hemolytic uremic syndrome (HUS), in which food-borne, Shiga toxin (STX)-producing E. coli lead to a systemic inflammatory and prothrombotic state, with complications which can include renal failure, seizures, coma, and death. In an in vitro model of HUS we have demonstrated that STX significantly augments functional TF on monolayers of human glomerular ECs (HGECs), and markedly enhances platelet strings (associated with ultra large vWF strings) and small aggregate formation on these monolayers. Specific Aim 1 is to determine the mechanism(s) of TF augmentation observed with exposure of activated HGECs to STX. Specific Aim 2 is to demonstrate that STX augments platelet adhesion/aggregation in flowing blood on activated HGECs via upregulation of the above adhesion molecules, but also via upregulation of the TF pathway. These studies should elucidate the potential of therapeutic interventions in HUS directed at blocking adhesion molecules and blocking EC surface and/or blood-borne TF. PUBLIC HEALTH RELEVANCE: We will test the hypothesis that the presence of certain molecules on vascular endothelium (the blood vessel wall) which are adhesive for blood platelets are what initiates platelet thrombus formation on the inflamed blood vessel wall. This thrombus formation is then amplified by the clotting activity known as tissue factor, expressed on the surface of this same inflamed endothelium. A prime application of this hypothesis, we believe, is the epidemic childhood hemolytic uremic syndrome (HUS), in which food- borne toxin-producing E. coli leads to a disease state with complications including kidney failure, seizures, coma, and death. Our studies promise to clarify the potential of treatments for HUS directed at blocking the above adhesive molecules and vessel wall tissue factor.

描述（由申请人提供）：在体内，活化内皮上的血小板粘附/聚集可能通过血小板粘附的内皮细胞（EC）分子，特别是1v 23（玻连蛋白受体）、ICAM-1、P-选择素和超大血管性血友病因子（vWF）串的上调而进行，伴随并随后是组织因子（TF）驱动的动脉或小动脉中的附壁血小板血栓形成。必要的EC活化可以通过几种途径产生，包括氧化的低密度脂蛋白、细菌毒素和/或细胞因子。目前的工作将测试的假设和范例，这些粘附分子的上调允许血小板粘附/聚集在内皮上，然后通过EC相关的TF和血液传播的TF放大的过程的开始。血源性TF以来源于白细胞、血小板和内皮细胞的微粒形式存在。EC相关型TF的上调可能通过多种机制发生，在此研究：a）TF mRNA稳定性增加和/或TFPI mRNA稳定性降低，B）EC膜外小叶上磷脂酰丝氨酸的增强，和c）EC相关TFPI的调节能力降低。我们进一步假设，壁血小板血栓，反过来，减慢血流足以让激活的内皮细胞承担一个更促凝表型。这种模式的一个典型例子是流行性儿童溶血性尿毒综合征（HUS），其中食源性、产生滋贺毒素（STX）的E。大肠杆菌导致全身炎症和血栓前状态，并发症包括肾衰竭、癫痫、昏迷和死亡。在HUS的体外模型中，我们已经证明STX显著增强人肾小球EC（HGEC）单层上的功能性TF，并且显著增强这些单层上的血小板串（与超大vWF串相关）和小聚集体形成。具体目标1是确定在活化的HGECs暴露于STX时观察到的TF增加的机制。具体目的2是证明STX通过上调上述粘附分子以及通过上调TF途径来增强活化的HGEC上流动血液中的血小板粘附/聚集。这些研究应阐明针对阻断粘附分子和阻断EC表面和/或血源性TF的HUS治疗干预的潜力。公共卫生相关性：我们将检验以下假设：血管内皮（血管壁）上某些分子的存在是血小板的粘合剂，是引发炎症血管壁上血小板血栓形成的原因。这种血栓形成随后被称为组织因子的凝血活性放大，组织因子表达在同一发炎内皮细胞的表面上。我们认为，这一假说的一个主要应用是流行性儿童溶血性尿毒综合征（HUS），其中食源性产毒素大肠杆菌。大肠杆菌导致一种疾病状态，并发症包括肾衰竭、癫痫、昏迷和死亡。我们的研究有望阐明针对上述粘附分子和血管壁组织因子的HUS治疗的潜力。