Induction of Tissue Factor by Patient Sera in HUS

HUS 患者血清诱导组织因子

基本信息

批准号：
7229792
负责人：
Eric Franklin Grabowski
金额：
$ 21.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229792
关键词：
Active Sites Acute Acute Kidney Failure Adhesions Antibodies Beds Biological Models Blood Blood Platelets Blood flow Child Childhood Clinical Trials Coagulation Process Coma Commit Condition Coupled Critiques Cultured Cells Data Deposition Diarrhea Disease Endothelial Cells Ensure Epithelial Cells Escherichia coli Event Factor VIIa Factor Xa Fibrin Foxes Functional disorder Gastrointestinal tract structure Generations Grant Hematologist Hemolysis Hemolytic Anemia Hemolytic-Uremic Syndrome Hemophilia A Hemostatic Agents Human In Vitro Injury Interruption Intestines Kidney Kidney Failure Laboratories Measures Mediating Modeling Necrosis Numbers Organ Oryctolagus cuniculus Pathway interactions Patient Recruitments Patients Performance Phase Plasma Play Protocols documentation Rate Recombinants Role Sampling Seizures Series Serum Shiga Toxin Shiga-Like Toxin I Societies Stroke Supportive care Surface TFPI Testing Thrombocytopenia Thromboplastin Thrombosis Thrombus Tissues Triad Acrylic Resin Tumor Necrosis Factor-alpha Up-Regulation Work activated Protein C base cell injury cytokine human TNF protein inhibitor/antagonist monolayer novel novel strategies response

项目摘要

DESCRIPTION (provided by applicant): Diarrhea-positive Hemolytic Uremic Syndrome (D+ HUS) is a serious disease in children that causes hemolytic anemia, thrombocytopenia, and acute renal failure. In fact, it is the most common cause of acute renal failure in children. During the acute phase of the HUS, some 3 to 5% of patients die, while as many as 25% also suffer stroke, seizures, and/or coma. At present this condition has little established pathophysiology, aside from an association with shiga toxin produced by strains of Escherichia coli and the presence of plasma markers indicative of a prothrombotic state. We have previously demonstrated that shiga toxin significantly increases the expression of functional tissue factor (TF) by TNF-alpha-activated human glomerular endothelial cells (HGECs). Therefore, we hypothesize that increased TF activity plays an important role in the pathophysiology of HUS. Through this grant we aim 1) to demonstrate that kidney sections from a rabbit model of HUS are prothrombotic as compared to control kidney tissue; 2) to demonstrate that sera from patients with HUS augment the expression of TF, while the blood of these patients contains TF-positive circulating endothelial cells and microparticles; and 3) to use monolayers of HGECs, patient platelet adhesion/aggregation in flowing blood, and kidney from the rabbit model to test inhibitors of the TF pathway as potential therapies for HUS. These inhibitors include recombinant-TF pathway inhibitor, an antibody directed against activated factor X, recombinant-activated protein C, and active site-inhibited r-factor VIIa. A confirmation that shiga toxin and cytokines present in patient sera augment the TF pathway in our model system coupled with a demonstration that pharmacologic interruption of this pathway is both effective and feasible, will help to develop a novel, effective therapy for childhood HUS, where at present only supportive care is available. A key additional feature of this proposal is the use of our newly formed collaborative group of pediatric nephrologists to facilitate patient recruitment

描述（由申请人提供）：腹泻阳性溶血性尿毒症综合征（D+ HUS）是一种严重的疾病，导致溶血性贫血，血小板减少症和急性肾衰竭。实际上，这是儿童急性肾衰竭的最常见原因。在HUS的急性阶段，约3至5％的患者死亡，而多达25％的患者也遭受中风，癫痫发作和/或昏迷。目前，这种情况几乎没有建立的病理生理学，除了与大肠杆菌菌株产生的shiga毒素的关联以及具有血栓性状态的血浆标志物的存在。我们先前已经证明，志贺毒素通过TNF-Alpha激活的人肾小球内皮细胞（HGEC）显着增加了功能组织因子（TF）的表达。因此，我们假设增加TF活性在HUS的病理生理中起着重要作用。通过这笔赠款，我们的目标是1）证明，与对照肾脏组织相比，来自HUS兔模型的肾脏切片是血栓形成的； 2）证明来自HUS患者的血清增强了TF的表达，而这些患者的血液含有TF阳性循环的内皮细胞和微粒； 3）使用HGEC的单层，流量血液中的患者血小板粘附/聚集以及兔模型的肾脏测试TF途径的抑制剂作为HUS的潜在疗法。这些抑制剂包括重组TF途径抑制剂，一种针对活化因子X的抗体，重组激活的蛋白C和活动抑制的现场抑制R-因子VIIA。确认患者血清中存在的志贺毒素和细胞因子增加了我们的模型系统中的TF途径，再加上该途径的药理学中断既有效又可行，这将有助于开发针对儿童HUS的新颖，有效的治疗方法，目前仅可获得支持。该提案的一个主要附加特征是使用我们新成立的儿科肾病学家的合作群体来促进患者招募