Induction of Tissue Factor by Patient Sera in HUS

HUS 患者血清诱导组织因子

• 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
• 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

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综合征（D+ HUS）是一种严重的儿童疾病，可引起溶血性贫血、血小板减少和急性肾衰竭。事实上，它是儿童急性肾衰竭最常见的原因。在HUS的急性期，约3%至5%的患者死亡，而多达25%的患者还患有中风，癫痫发作和/或昏迷。目前，除了与大肠杆菌菌株产生的滋贺毒素和存在指示血栓前状态的血浆标志物有关外，这种情况几乎没有确定的病理生理学。我们以前已经证明，滋贺毒素显着增加TNF-α激活的人肾小球内皮细胞（HGECs）的功能性组织因子（TF）的表达。因此，我们推测TF活性增加在HUS的病理生理学中起重要作用。通过这项授权，我们的目的是1）证明来自HUS兔模型的肾切片与对照肾组织相比是促血栓形成的; 2）证明来自HUS患者的血清增加TF的表达，而这些患者的血液含有TF阳性循环内皮细胞和微粒;和3）使用HGECs单层、流动血液中的患者血小板粘附/聚集和来自兔模型的肾脏来测试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、针对活化因子X的抗体、重组活化蛋白C和活性位点抑制的r-因子VIIa。在我们的模型系统中，患者血清中存在的滋贺毒素和细胞因子增加了TF通路，并证明了该通路的药理学中断是有效和可行的，这将有助于开发一种新的有效治疗儿童HUS的方法，目前只有支持性治疗可用。该提案的一个关键附加功能是使用我们新成立的儿科肾病学家协作组来促进患者招募